dbSNP rs2232191: GJA5:p.Tyr123Tyr (chr1-147758870-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_181703.4(GJA5):c.369C>T(p.Tyr123Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,614,154 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0066 ( 72 hom. )

Consequence

GJA5
NM_181703.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.00500

Publications

5 publications found

Variant links:

Genes affected

GJA5 (HGNC:4279): (gap junction protein alpha 5) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]

GJA5 Gene-Disease associations (from GenCC):

atrial fibrillation, familial, 11
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

GJA5 links:

ENSG00000294222 (HGNC:):

ENSG00000294222 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 1-147758870-G-A is Benign according to our data. Variant chr1-147758870-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.005 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00663 (1009/152300) while in subpopulation EAS AF = 0.0515 (266/5168). AF 95% confidence interval is 0.0464. There are 13 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1009 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181703.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA5	NM_181703.4	MANE Select	c.369C>T	p.Tyr123Tyr	synonymous	Exon 2 of 2	NP_859054.1	P36382
	GJA5	NM_005266.7		c.369C>T	p.Tyr123Tyr	synonymous	Exon 2 of 2	NP_005257.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJA5	ENST00000579774.3	TSL:1 MANE Select	c.369C>T	p.Tyr123Tyr	synonymous	Exon 2 of 2	ENSP00000463851.1	P36382
GJA5	ENST00000621517.1	TSL:2	c.369C>T	p.Tyr123Tyr	synonymous	Exon 2 of 2	ENSP00000484552.1	P36382
GJA5	ENST00000863529.1		c.369C>T	p.Tyr123Tyr	synonymous	Exon 2 of 2	ENSP00000533588.1

Frequencies

GnomAD3 genomes

AF:

0.00664

AC:

1011

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00929

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.0515

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00628

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00920

AC:

2311

AN:

251114

AF XY:

0.00925

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00651

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.0484

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00639

Gnomad OTH exome

AF:

0.00685

GnomAD4 exome

AF:

0.00658

AC:

9625

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00673

AC XY:

4893

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33478

American (AMR)

AF:

0.00660

AC:

295

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

412

AN:

26136

East Asian (EAS)

AF:

0.0384

AC:

1524

AN:

39700

South Asian (SAS)

AF:

0.00844

AC:

728

AN:

86258

European-Finnish (FIN)

AF:

0.00163

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00538

AC:

5983

AN:

1111976

Other (OTH)

AF:

0.00871

AC:

526

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

677

1355

2032

2710

3387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.00663

AC:

1009

AN:

152300

Hom.:

Cov.:

AF XY:

0.00669

AC XY:

498

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41568

American (AMR)

AF:

0.00928

AC:

142

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3470

East Asian (EAS)

AF:

0.0515

AC:

266

AN:

5168

South Asian (SAS)

AF:

0.0102

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00628

AC:

427

AN:

68034

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00710

Hom.:

Bravo

AF:

0.00735

EpiCase

AF:

0.00791

EpiControl

AF:

0.00859

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Atrial fibrillation, familial, 11;C4551959:Atrial standstill 1 (1)

Familial atrial fibrillation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.96

(source)

DANN

Benign

0.75

PhyloP100

-0.0050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over