chr1-147908759-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005267.5(GJA8):c.804C>T(p.Leu268Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,614,040 control chromosomes in the GnomAD database, including 1,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 206 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1437 hom. )

Consequence

GJA8
NM_005267.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.442

Publications

12 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 1-147908759-C-T is Benign according to our data. Variant chr1-147908759-C-T is described in ClinVar as Benign. ClinVar VariationId is 259707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.442 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA8	NM_005267.5 link	c.804C>T	p.Leu268Leu	synonymous_variant	Exon 2 of 2	ENST00000369235.2	NP_005258.2	P48165X5D7G1
GJA8	XM_011509417.3 link	c.804C>T	p.Leu268Leu	synonymous_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.804C>T	p.Leu268Leu	synonymous_variant	Exon 2 of 2	6	NM_005267.5	ENSP00000358238.1		P48165

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

7171

AN:

152136

Hom.:

204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0709

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0245

Gnomad ASJ

AF:

0.0496

Gnomad EAS

AF:

0.0491

Gnomad SAS

AF:

0.0660

Gnomad FIN

AF:

0.0382

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0385

Gnomad OTH

AF:

0.0378

GnomAD2 exomes

AF:

0.0403

AC:

10130

AN:

251406

AF XY:

0.0410

show subpopulations

Gnomad AFR exome

AF:

0.0734

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0509

Gnomad EAS exome

AF:

0.0344

Gnomad FIN exome

AF:

0.0358

Gnomad NFE exome

AF:

0.0362

Gnomad OTH exome

AF:

0.0438

GnomAD4 exome

AF:

0.0418

AC:

61056

AN:

1461786

Hom.:

1437

Cov.:

AF XY:

0.0422

AC XY:

30699

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0758

AC:

2537

AN:

33474

American (AMR)

AF:

0.0165

AC:

738

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0477

AC:

1246

AN:

26136

East Asian (EAS)

AF:

0.0450

AC:

1788

AN:

39700

South Asian (SAS)

AF:

0.0680

AC:

5864

AN:

86252

European-Finnish (FIN)

AF:

0.0377

AC:

2013

AN:

53416

Middle Eastern (MID)

AF:

0.0475

AC:

274

AN:

5768

European-Non Finnish (NFE)

AF:

0.0395

AC:

43878

AN:

1111930

Other (OTH)

AF:

0.0450

AC:

2718

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3669

7338

11007

14676

18345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1740

3480

5220

6960

8700

<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:

0.0472

AC:

7181

AN:

152254

Hom.:

206

Cov.:

AF XY:

0.0479

AC XY:

3566

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0710

AC:

2950

AN:

41544

American (AMR)

AF:

0.0245

AC:

375

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0496

AC:

172

AN:

3468

East Asian (EAS)

AF:

0.0490

AC:

253

AN:

5164

South Asian (SAS)

AF:

0.0663

AC:

320

AN:

4826

European-Finnish (FIN)

AF:

0.0382

AC:

405

AN:

10616

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0385

AC:

2616

AN:

68016

Other (OTH)

AF:

0.0369

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

339

679

1018

1358

1697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0422

Hom.:

330

Bravo

AF:

0.0453

Asia WGS

AF:

0.0950

AC:

329

AN:

3478

EpiCase

AF:

0.0354

EpiControl

AF:

0.0343

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cataract 1 multiple types

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Zonular Pulverulent Cataract

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

2.6

(source)

DANN

Benign

0.70

PhyloP100

0.44

Mutation Taster

=100/0

polymorphism (auto)

(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