chr1-228158352-C-T

Variant names:

Variant summary

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

The NM_020435.4(GJC2):c.594C>T(p.His198His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,588,150 control chromosomes in the GnomAD database, including 1,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 68 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1263 hom. )

Consequence

GJC2
NM_020435.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.273

Publications

3 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 1-228158352-C-T is Benign according to our data. Variant chr1-228158352-C-T is described in ClinVar as Benign. ClinVar VariationId is 241298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.273 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0251 (3808/151878) while in subpopulation NFE AF = 0.0417 (2834/67902). AF 95% confidence interval is 0.0405. There are 68 homozygotes in GnomAd4. There are 1761 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 68 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJC2	NM_020435.4 link	c.594C>T	p.His198His	synonymous_variant	Exon 2 of 2	ENST00000366714.3	NP_065168.2	Q5T442A0A654IBV7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3 link	c.594C>T	p.His198His	synonymous_variant	Exon 2 of 2	1	NM_020435.4	ENSP00000355675.2		Q5T442

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3813

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00717

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.0289

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0385

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0418

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0294

AC:

6109

AN:

207860

AF XY:

0.0313

show subpopulations

Gnomad AFR exome

AF:

0.00642

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.000256

Gnomad FIN exome

AF:

0.0200

Gnomad NFE exome

AF:

0.0418

Gnomad OTH exome

AF:

0.0305

GnomAD4 exome

AF:

0.0393

AC:

56385

AN:

1436272

Hom.:

1263

Cov.:

AF XY:

0.0396

AC XY:

28255

AN XY:

713512

show subpopulations

African (AFR)

AF:

0.00499

AC:

165

AN:

33084

American (AMR)

AF:

0.0107

AC:

449

AN:

41942

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

601

AN:

25762

East Asian (EAS)

AF:

0.000155

AC:

AN:

38820

South Asian (SAS)

AF:

0.0438

AC:

3713

AN:

84722

European-Finnish (FIN)

AF:

0.0220

AC:

953

AN:

43328

Middle Eastern (MID)

AF:

0.0233

AC:

129

AN:

5540

European-Non Finnish (NFE)

AF:

0.0438

AC:

48372

AN:

1103496

Other (OTH)

AF:

0.0335

AC:

1997

AN:

59578

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3475

6950

10426

13901

17376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1808

3616

5424

7232

9040

<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:

0.0251

AC:

3808

AN:

151878

Hom.:

Cov.:

AF XY:

0.0237

AC XY:

1761

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.00715

AC:

297

AN:

41536

American (AMR)

AF:

0.0106

AC:

162

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0289

AC:

100

AN:

3466

East Asian (EAS)

AF:

0.000581

AC:

AN:

5162

South Asian (SAS)

AF:

0.0383

AC:

185

AN:

4824

European-Finnish (FIN)

AF:

0.0162

AC:

168

AN:

10398

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0417

AC:

2834

AN:

67902

Other (OTH)

AF:

0.0128

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

188

376

563

751

939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0343

Hom.:

Bravo

AF:

0.0229

Asia WGS

AF:

0.0160

AC:

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2016

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. -

Dec 26, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Jan 20, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.5

(source)

DANN

Benign

0.60

PhyloP100

-0.27

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