rs138140155

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 2P and 18B. PP2PP3BP4_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

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

cataract 1 multiple types
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
cataract - microcornea syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset sutural cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulverulent cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GJA8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Trascript score misZ: -0.35816 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 1 multiple types, cataract - microcornea syndrome, early-onset nuclear cataract, early-onset sutural cataract, pulverulent cataract, total early-onset cataract.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

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 VariationId is 217323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA8	NM_005267.5 link	c.658A>G	p.Asn220Asp	missense_variant	Exon 2 of 2	ENST00000369235.2	NP_005258.2	P48165X5D7G1
GJA8	XM_011509417.3 link	c.658A>G	p.Asn220Asp	missense_variant	Exon 1 of 2		XP_011507719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA8	ENST00000369235.2 link	c.658A>G	p.Asn220Asp	missense_variant	Exon 2 of 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

GnomAD2 exomes

AF:

0.00229

AC:

575

AN:

251474

AF XY:

0.00237

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 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

African (AFR)

AF:

0.000478

AC:

AN:

33478

American (AMR)

AF:

0.000604

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00221

AC:

118

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00415

AC:

4614

AN:

1112002

Other (OTH)

AF:

0.00212

AC:

128

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

292

585

877

1170

1462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00232

AC:

353

AN:

152110

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

150

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

41500

American (AMR)

AF:

0.000785

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00424

AC:

288

AN:

67984

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00312

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26694549, 19182255, 28827829, 29464339) -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GJA8: BS1 -

Cataract 1 multiple types

Benign:3

Jan 21, 2023

Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

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 -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Sep 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GJA8-related disorder

Benign:1

Feb 17, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental cataract

Benign:1

Jan 09, 2015

Eye Genetics Research Group, Children's Medical Research Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

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

(source)

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

PhyloP100

9.2

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

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over