rs201162411

Positions:

• chr16-57901371-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP5 BP4

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:2
• Conservation: PhyloP100: 3.28

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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: {Uncertain_significance=2, Pathogenic=9, Likely_pathogenic=3}. 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.

Transcripts

RefSeq

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

Ensembl

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

GnomAD3 exomes AF: 0.00114 AC: 285 AN: 249524 Hom.: 0 AF XY: 0.00103 AC XY: 139 AN XY: 135380

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.: 4 Cov.: 33 AF XY: 0.00109 AC XY: 791 AN XY: 727234

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.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74476

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.: 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:18 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Pathogenic:6

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	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
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	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:4 Uncertain: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	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	- -

Retinitis pigmentosa 45 Pathogenic:4 Uncertain:1

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. -
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]. -
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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	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	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;.
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
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

Other links and lift over

dbSNP: rs201162411; hg19: chr16-57935275;