rs201162411

Variant names:

• chr16-57901371-T-A
• rs201162411
• NM_001297.5:c.2957A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_001297.5(CNGB1):​c.2957A>T​(p.Asn986Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,166 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N986N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: CNGB1 NM_001297.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21 U:2
• Conservation: PhyloP100: 3.28
• Publications: 26 publications found

Genes affected

CNGB1 (HGNC:2151): (cyclic nucleotide gated channel subunit beta 1) In humans, the rod photoreceptor cGMP-gated cation channel helps regulate ion flow into the rod photoreceptor outer segment in response to light-induced alteration of the levels of intracellular cGMP. This channel consists of two subunits, alpha and beta, with the protein encoded by this gene representing the beta subunit. Defects in this gene are a cause of cause of retinitis pigmentosa type 45. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

CNGB1 Gene-Disease associations (from GenCC):

• CNGB1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 45

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP5: Variant 16-57901371-T-A is Pathogenic according to our data. Variant chr16-57901371-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166891.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08802411). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00119 (1739/1461870) while in subpopulation MID AF = 0.00312 (18/5764). AF 95% confidence interval is 0.00202. There are 4 homozygotes in GnomAdExome4. There are 791 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB1	NM_001297.5	c.2957A>T	p.Asn986Ile	missense_variant	Exon 29 of 33	ENST00000251102.13	NP_001288.3
CNGB1	NM_001286130.2	c.2939A>T	p.Asn980Ile	missense_variant	Exon 29 of 33		NP_001273059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB1	ENST00000251102.13	c.2957A>T	p.Asn986Ile	missense_variant	Exon 29 of 33	1	NM_001297.5	ENSP00000251102.8
CNGB1	ENST00000564448.5	c.2939A>T	p.Asn980Ile	missense_variant	Exon 29 of 33	1		ENSP00000454633.1
CNGB1	ENST00000565942.1	c.2A>T	p.Asn1Ile	missense_variant	Exon 1 of 4	5		ENSP00000455964.1
CNGB1	ENST00000569643.1	n.614A>T		non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00114 AC: 285 AN: 249524 AF XY: 0.00103

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00626

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00119 AC: 1739 AN: 1461870 Hom.: 4 Cov.: 33 AF XY: 0.00109 AC XY: 791 AN XY: 727234

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00623 AC: 333 AN: 53414

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.00115 AC: 1278 AN: 1112000

Other (OTH) AF: 0.00123 AC: 74 AN: 60394

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74476

African (AFR) AF: 0.000289 AC: 12 AN: 41576

American (AMR) AF: 0.000654 AC: 10 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00659 AC: 70 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.000838 AC: 7

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.000872

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:21 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Pathogenic:8

Aug 25, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CNGB1 c.2957A>T (p.Asn986Ile) missense variant has been reported in two studies in which it is found in six unrelated individuals with an autosomal recessive form of retinitis pigmentosa, including in four in a homozygous state and in two in a compound heterozygous state (Simpson et al. 2011; Hull et al. 2017). Common phenotypes in these individuals included night blindness with an onset in infancy or childhood, loss of peripheral vision in adulthood, and based on a fundus exam, a majority of patients had optic disc pallor, retinal pigment epithelium atrophy, and intraretinal pigment migration. The two individuals with the variant in a compound heterozygous state also had affected siblings with the same variants, one affected sister in one family and an additional affected brother and sister in the second family (Hull et al. 2017). The p.Asn986Ile variant was absent from 720 control chromosomes (Simpson et al. 2011) and is reported at a frequency of 0.00652 in the European (Finnish) population of the Genome Aggregation Database. Based on the clinical evidence, the p.Asn986Ile variant is classified as pathogenic for an autosomal recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 27, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn986Ile variant in CNGB1 has been reported in multiple individuals with retinitis pigmentosa, all of whom were homozygous or compound heterozygous with a second CNGB1 variant (Simpson 2011, PMID: 21147909; Abu-Safieh 2013, PMID: 23105016; Carss 2017, PMID: 28041643; Stone 2017, PMID: 28559085; Hull 2017, PMID: 28056120; Fuster-Garcia 2019, PMID: 31725169; Jespersgaad 2019, PMID: 30718709; Radojevic 2020, DOI: 10.1080/13816810.2020.1832532). This variant also segregated with disease in 6 affected individuals from 5 families (Hull, 2017, PMID: 28056120; Fuster-Garcia, 2019, PMID: 31725169; Radojevic, 2020, DOI: 10.1080/13816810.2020.1832532). This variant has been identified in 0.635% (159/25032) of European (Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org) with no cases of homozygosity and a frequency low enough to be consistent with a recessive allele frequency for this gene. This variant has also been reported in ClinVar (Variation ID 166891). Computational prediction tools and conservation analyses support that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PP3. -

Apr 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CNGB1 c.2957A>T (p.Asn986Ile) results in a non-conservative amino acid change located in the Cyclic nucleotide-monophosphate binding domain (IPR000595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 249524 control chromosomes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGB1 causing Retinitis Pigmentosa phenotype (0.00063). c.2957A>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa (example, Jackson_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35743231). ClinVar contains an entry for this variant (Variation ID: 166891). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 01, 2024

Lab De Baere, Eye and Developmental Genetics Lab, Ghent University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG/AMP guidelines: PS4, PP5, PP3, PP1, PM3_2 -

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Asn986Ile variant in CNGB1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS4, PM3, PP1, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:4 Uncertain:1

Apr 27, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 986 of the CNGB1 protein (p.Asn986Ile). This variant is present in population databases (rs201162411, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 21147909, 28041643, 28056120, 28559085, 29912909). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 166891). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CNGB1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37510321, 36460718, 36819107, 33749171, 34906470, 23105016, 32483926, 32531858, 37644014, 37734845, 28056120, 26355662, 21147909, 29912909, 23977260, 24015210, 29068140, 28559085, 28041643, 30718709, 31725169, 31456290, 33465333, 34426522, 31570810, 33576794, 33847019, 32037395, 35836572, 38347443, 39062705, 38219857) -

Retinitis pigmentosa 45 Pathogenic:4 Uncertain:1

Mar 23, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The CNGB1 c.2957A>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS4, PM3, PP1, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic. -

Retinal dystrophy Pathogenic:2

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CNGB1-related disorder Pathogenic:1

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CNGB1 c.2957A>T variant is predicted to result in the amino acid substitution p.Asn986Ile. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with retinitis pigmentosa (see for example, Table 2, Simpson et al. 2011. PubMed ID: 21147909; Table S1, Stone et al. 2017. PubMed ID: 28559085; Table S4, Jespersgaard et al. 2019. PubMed ID: 30718709). This variant is reported in 0.64% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Autosomal recessive retinitis pigmentosa Pathogenic:1

Sep 10, 2015

Faculty of Health Sciences, Beirut Arab University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

CNGB1-related retinopathy Pathogenic:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.1	M;.
PhyloP100		3.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;.
Vest4		0.92
MVP		0.67
MPC		0.53
ClinPred		0.14	T
GERP RS		5.2
PromoterAI		-0.025	Neutral
Varity_R		0.89
gMVP		0.64
Mutation Taster		=34/66	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201162411; hg19: chr16-57935275;