chr13-20189104-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM1PP2BP4_ModerateBP6

The NM_004004.6(GJB2):c.478G>A(p.Gly160Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000699 in 1,614,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G160R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:12

Conservation

PhyloP100: 6.12

Publications

25 publications found

Variant links:

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

GJB2 Gene-Disease associations (from GenCC):

Bart-Pumphrey syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
ichthyosis, hystrix-like, with hearing loss
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
keratoderma hereditarium mutilans
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
palmoplantar keratoderma-deafness syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
autosomal recessive nonsyndromic hearing loss 1A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
autosomal dominant keratitis-ichthyosis-hearing loss syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
autosomal dominant nonsyndromic hearing loss 3A
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
KID syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GJB2 links:

ENSG00000296095 (HGNC:):

ENSG00000296095 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 13 uncertain in NM_004004.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 111 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: -0.72044 (below the threshold of 3.09). Trascript score misZ: 0.4379 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 1A, ichthyosis, hystrix-like, with hearing loss, keratoderma hereditarium mutilans, hearing loss, autosomal recessive, Bart-Pumphrey syndrome, palmoplantar keratoderma-deafness syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss, KID syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.12778345).

BP6

Variant 13-20189104-C-T is Benign according to our data. Variant chr13-20189104-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44755.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004004.6. 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
	GJB2	NM_004004.6	MANE Select	c.478G>A	p.Gly160Ser	missense	Exon 2 of 2	NP_003995.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GJB2	ENST00000382848.5	TSL:1 MANE Select	c.478G>A	p.Gly160Ser	missense	Exon 2 of 2	ENSP00000372299.4
GJB2	ENST00000382844.2	TSL:6	c.478G>A	p.Gly160Ser	missense	Exon 1 of 1	ENSP00000372295.1
GJB2	ENST00000906230.1		c.478G>A	p.Gly160Ser	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000705

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000558

AC:

140

AN:

251098

AF XY:

0.000589

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000617

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000667

AC:

975

AN:

1461786

Hom.:

Cov.:

AF XY:

0.000635

AC XY:

462

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33480

American (AMR)

AF:

0.000581

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000711

AC:

791

AN:

1111994

Other (OTH)

AF:

0.000977

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.00101

AC:

154

AN:

152268

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

41542

American (AMR)

AF:

0.000785

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000772

Hom.:

Bravo

AF:

0.00120

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000527

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00113

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (5)

Autosomal recessive nonsyndromic hearing loss 1A (4)

Autosomal dominant nonsyndromic hearing loss 3A (2)

Ichthyosis, hystrix-like, with hearing loss (2)

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome (1)

GJB2-related disorder (1)

Nonsyndromic Deafness (1)

Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.13

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

PhyloP100

6.1

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.77

Sift

Benign

0.060

Sift4G

Uncertain

0.053

Polyphen

0.97

Vest4

0.42

MVP

0.98

MPC

0.20

ClinPred

0.042

GERP RS

5.5

Varity_R

0.60

gMVP

0.92

Mutation Taster

=14/86

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over