1-147908696-T-G

Position:

chr1-147908696-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005267.5(GJA8):c.741T>G(p.Ile247Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,613,980 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 22 hom. )

Consequence

GJA8
NM_005267.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: -2.36

Variant links:

Genes affected

GJA8 (HGNC:4281): (gap junction protein alpha 8) This gene encodes a transmembrane connexin protein that is necessary for lens growth and maturation of lens fiber cells. The encoded protein is a component of gap junction channels and functions in a calcium and pH-dependent manner. Mutations in this gene have been associated with zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. [provided by RefSeq, Dec 2009]

GJA8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037556887).

BP6

Variant 1-147908696-T-G is Benign according to our data. Variant chr1-147908696-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 8723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-147908696-T-G is described in Lovd as [Likely_benign]. Variant chr1-147908696-T-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00349 (531/152142) while in subpopulation NFE AF= 0.00415 (282/68004). AF 95% confidence interval is 0.00375. There are 3 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA8	NM_005267.5 linkuse as main transcript	c.741T>G	p.Ile247Met	missense_variant	2/2	ENST00000369235.2	NP_005258.2
GJA8	XM_011509417.3 linkuse as main transcript	c.741T>G	p.Ile247Met	missense_variant	1/2		XP_011507719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA8	ENST00000369235.2 linkuse as main transcript	c.741T>G	p.Ile247Met	missense_variant	2/2		NM_005267.5	ENSP00000358238	P1

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

531

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00415

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00348

AC:

876

AN:

251392

Hom.:

AF XY:

0.00357

AC XY:

485

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0178

Gnomad NFE exome

AF:

0.00384

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00356

AC:

5202

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

2559

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.0156

Gnomad4 NFE exome

AF:

0.00375

Gnomad4 OTH exome

AF:

0.00207

GnomAD4 genome

AF:

0.00349

AC:

531

AN:

152142

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

290

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000723

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.0191

Gnomad4 NFE

AF:

0.00415

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00356

Hom.:

Bravo

AF:

0.00199

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00316

AC:

384

EpiCase

AF:

0.00382

EpiControl

AF:

0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 1 multiple types

Pathogenic:1Benign:3

Likely benign, criteria provided, single submitter	curation	Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania	Jan 21, 2023	Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: BS1, BP4, BP5. Original variant report: PMID:11846744;1975179;23508780. The cataract phenotype/s reported for this variant are: Pulverulent, and diffuse white opacities. Proband reported with this variant has an alternate variant in CRYBB1 reported to be causative. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2001	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 12, 2023	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GJA8: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

GJA8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.0080

DANN

Benign

0.85

DEOGEN2

Benign

0.16

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.56

MetaRNN

Benign

0.038

MetaSVM

Uncertain

0.042

MutationAssessor

Benign

0.69

MutationTaster

Benign

2.4e-7

A;A

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.090

REVEL

Benign

0.28

Sift

Benign

0.15

Sift4G

Benign

0.34

Polyphen

0.47

Vest4

0.13

MVP

0.57

ClinPred

0.010

GERP RS

-3.6

Varity_R

0.11

gMVP

0.41

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