1-147908613-A-G

Position:

chr1-147908613-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_005267.5(GJA8):c.658A>G(p.Asn220Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,613,986 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 16 hom. )

Consequence

GJA8
NM_005267.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 9.18

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20916966).

BP6

Variant 1-147908613-A-G is Benign according to our data. Variant chr1-147908613-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 217323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-147908613-A-G is described in Lovd as [Likely_benign]. Variant chr1-147908613-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (353/152110) while in subpopulation NFE AF= 0.00424 (288/67984). AF 95% confidence interval is 0.00383. There are 1 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA8	NM_005267.5 linkuse as main transcript	c.658A>G	p.Asn220Asp	missense_variant	2/2	ENST00000369235.2	NP_005258.2	P48165X5D7G1
GJA8	XM_011509417.3 linkuse as main transcript	c.658A>G	p.Asn220Asp	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.658A>G	p.Asn220Asp	missense_variant	2/2	6	NM_005267.5	ENSP00000358238.1		P48165

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

353

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00424

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00229

AC:

575

AN:

251474

Hom.:

AF XY:

0.00237

AC XY:

322

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.00413

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00336

AC:

4906

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

2371

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00221

Gnomad4 NFE exome

AF:

0.00415

Gnomad4 OTH exome

AF:

0.00212

GnomAD4 genome

AF:

0.00232

AC:

353

AN:

152110

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

150

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000627

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00424

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00327

Hom.:

Bravo

AF:

0.00217

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00257

AC:

312

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00344

ClinVar

Significance: Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	This variant is associated with the following publications: (PMID: 26694549, 19182255, 28827829, 29464339) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	GJA8: BS1 -

Cataract 1 multiple types

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
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, PP3. Original variant report: PMID:28827829;29464339. The cataract phenotype reported for this variant is: Nuclear and cortical. Additional phenotype/s reported in these individual/s are: aphakic glaucoma. Proband reported with this variant has no cataract; Microphthalmia, coloboma, retrobulbar cysts, microcephaly associated with normal development, reduced growth. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Cataract 1 multiple types;C2675897:Chromosome 1q21.1 deletion syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

GJA8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

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). -

Zonular Pulverulent Cataract

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Developmental cataract

Benign:1

Benign, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Jan 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.21

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.99

MVP

0.97

ClinPred

0.060

GERP RS

4.4

Varity_R

0.60

gMVP

0.97

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