Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The ENST00000366714.3(GJC2):c.528G>A(p.Glu176Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000679 in 1,533,678 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00094 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 8 hom. )

Consequence

GJC2
ENST00000366714.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.948

Publications

0 publications found

Variant links:

Genes affected

GJC2 (HGNC:17494): (gap junction protein gamma 2) This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. [provided by RefSeq, Jul 2008]

GJC2 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
lymphatic malformation 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
hereditary spastic paraplegia 44
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
lymphatic malformation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GJC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 1-228158286-G-A is Benign according to our data. Variant chr1-228158286-G-A is described in ClinVar as Benign. ClinVar VariationId is 458297.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.948 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00094 (143/152124) while in subpopulation EAS AF = 0.0151 (78/5160). AF 95% confidence interval is 0.0124. There are 2 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366714.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	NM_020435.4	MANE Select	c.528G>A	p.Glu176Glu	synonymous	Exon 2 of 2	NP_065168.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	ENST00000366714.3	TSL:1 MANE Select	c.528G>A	p.Glu176Glu	synonymous	Exon 2 of 2	ENSP00000355675.2

Frequencies

GnomAD3 genomes

AF:

0.000921

AC:

140

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0145

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00172

AC:

236

AN:

137028

AF XY:

0.00178

show subpopulations

Gnomad AFR exome

AF:

0.000275

Gnomad AMR exome

AF:

0.000285

Gnomad ASJ exome

AF:

0.000127

Gnomad EAS exome

AF:

0.0135

Gnomad FIN exome

AF:

0.00173

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000725

GnomAD4 exome

AF:

0.000650

AC:

898

AN:

1381554

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

467

AN XY:

680844

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

31450

American (AMR)

AF:

0.000140

AC:

AN:

35604

Ashkenazi Jewish (ASJ)

AF:

0.000161

AC:

AN:

24832

East Asian (EAS)

AF:

0.0109

AC:

386

AN:

35572

South Asian (SAS)

AF:

0.00190

AC:

151

AN:

79444

European-Finnish (FIN)

AF:

0.00184

AC:

AN:

38504

Middle Eastern (MID)

AF:

0.000443

AC:

AN:

4516

European-Non Finnish (NFE)

AF:

0.000207

AC:

222

AN:

1074212

Other (OTH)

AF:

0.000923

AC:

AN:

57420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000940

AC:

143

AN:

152124

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41562

American (AMR)

AF:

0.000523

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3464

East Asian (EAS)

AF:

0.0151

AC:

AN:

5160

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000324

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000518

Hom.:

Bravo

AF:

0.00105

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.60

(source)

DANN

Benign

0.32

PhyloP100

-0.95

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over