16-57901371-T-A

Position:

chr16-57901371-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP5BP4BS1_Supporting

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).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

CNGB1
NM_001297.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18U:2

Conservation

PhyloP100: 3.28

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a binding_site (size 139) in uniprot entity CNGB1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_001297.5

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 id is 166891.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=10, Uncertain_significance=2}. Variant chr16-57901371-T-A is described in Lovd as [Pathogenic]. Variant chr16-57901371-T-A is described in Lovd as [Likely_pathogenic]. Variant chr16-57901371-T-A is described in Lovd as [Likely_pathogenic]. Variant chr16-57901371-T-A is described in Lovd as [Pathogenic].

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. gnomad4_exome 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 gnomad4_exome. There are 791 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB1	NM_001297.5 link	c.2957A>T	p.Asn986Ile	missense_variant	29/33	ENST00000251102.13	NP_001288.3	Q14028-1
CNGB1	NM_001286130.2 link	c.2939A>T	p.Asn980Ile	missense_variant	29/33		NP_001273059.1	Q14028-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CNGB1	ENST00000251102.13 link	c.2957A>T	p.Asn986Ile	missense_variant	29/33	1	NM_001297.5	ENSP00000251102.8	Q14028-1
CNGB1	ENST00000564448.5 link	c.2939A>T	p.Asn980Ile	missense_variant	29/33	1		ENSP00000454633.1	Q14028-4
CNGB1	ENST00000565942.1 link	c.2A>T	p.Asn1Ile	missense_variant	1/4	5		ENSP00000455964.1	H3BQW3
CNGB1	ENST00000569643.1 link	n.614A>T		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152178

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00114

AC:

285

AN:

249524

Hom.:

AF XY:

0.00103

AC XY:

139

AN XY:

135380

show subpopulations

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 SAS exome

AF:

0.0000327

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.:

Cov.:

AF XY:

0.00109

AC XY:

791

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00623

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

152296

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00659

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000589

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000248

AC:

ESP6500EA

AF:

0.000838

AC:

ExAC

AF:

0.00110

AC:

133

EpiCase

AF:

0.000872

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:18Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinitis pigmentosa

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 25, 2017	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. -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	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. -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2021	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. -

not provided

Pathogenic:4Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2022	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: 23105016, 32483926, 32531858, 28056120, 26355662, 21147909, 29912909, 23977260, 24015210, 29068140, 28559085, 28041643, 30718709, 31725169, 31456290, 33465333, 34426522, 31570810, 33576794, 33847019, 32037395) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -

Retinitis pigmentosa 45

Pathogenic:4Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 15, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Mar 26, 2024	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 09, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -

CNGB1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

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

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Sep 10, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.088

T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.1

M;.

PrimateAI

Uncertain

0.62

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

GERP RS

5.2

Varity_R

0.89

gMVP

0.64

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over