8-86628994-A-C

Position:

chr8-86628994-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM2BP4_StrongBS1

The NM_019098.5(CNGB3):c.1405T>G(p.Tyr469Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000431 in 1,614,036 control chromosomes in the GnomAD database, including 1 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 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CNGB3
NM_019098.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:6

Conservation

PhyloP100: 4.11

Variant links:

Genes affected

CNGB3 (HGNC:2153): (cyclic nucleotide gated channel subunit beta 3) This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease. [provided by RefSeq, Feb 2010]

CNGB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a topological_domain Extracellular (size 65) in uniprot entity CNGB3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_019098.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041806072).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00244 (371/152284) while in subpopulation AFR AF= 0.00835 (347/41570). AF 95% confidence interval is 0.00762. There are 1 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5 link	c.1405T>G	p.Tyr469Asp	missense_variant	12/18	ENST00000320005.6	NP_061971.3	Q9NQW8-1
CNGB3	XM_011517138.3 link	c.991T>G	p.Tyr331Asp	missense_variant	10/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CNGB3	ENST00000320005.6 link	c.1405T>G	p.Tyr469Asp	missense_variant	12/18	1	NM_019098.5	ENSP00000316605.5	Q9NQW8-1
CNGB3	ENST00000681546.1 link	n.1225T>G		non_coding_transcript_exon_variant	7/13
CNGB3	ENST00000681746.1 link	n.1405T>G		non_coding_transcript_exon_variant	12/19			ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

371

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00837

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000589

AC:

148

AN:

251070

Hom.:

AF XY:

0.000487

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.00824

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000222

AC:

324

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

138

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00810

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.00244

AC:

371

AN:

152284

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

175

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00835

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.00279

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000782

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2023	Variant summary: CNGB3 c.1405T>G (p.Tyr469Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 251070 control chromosomes, predominantly at a frequency of 0.0082 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGB3 causing Achromatopsia phenotype (0.005), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1405T>G has been reported in the literature in settings of limited gene panel testing in heterozygous individuals with no reported second variant affected with achromatopsia (e.g. Mayer_2017, Weisschuh_2020), in at least one compound heterozygous individual affected with macular degeneration (e.g. Sun_2020, Nishiguchi_2005), or by WES in a heterozygous individual affected with severe Retinitis Pigmentosa (e.g. Ganapathi_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Achromatopsia. One publication reports experimental evidence evaluating an impact on protein function, suggesting the variant may enhance the intrinsic (ligand independent) gating properties of CNG channels in vitro, however, additional evidence is necessary to allow convincing conclusions about the variant effect in disease (e.g. Meighan_2015). The following publications have been ascertained in the context of this evaluation (PMID: 35672425, 28795510, 26106334, 15712225, 32913385, 31544997). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=2), likely benign (n=1), uncertain significance (n=1), or likely pathogenic (n=1). Based on the conflicting evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 05, 2024	The p.Tyr469Asp variant in CNGB3 is classified as likely benign because it has been identified in 0.8% (347/41448) of African chromosomes, including 1 homozygote by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

Achromatopsia 3

Pathogenic:1Uncertain:1

Likely pathogenic, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 19, 2017	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CNGB3: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Severe early-childhood-onset retinal dystrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

Achromatopsia

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.042

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

2.9

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-8.7

REVEL

Pathogenic

0.74

Sift

Benign

0.055

Sift4G

Uncertain

0.060

Polyphen

0.97

Vest4

0.92

MVP

0.98

MPC

0.17

ClinPred

0.12

GERP RS

4.8

Varity_R

0.41

gMVP

0.79

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