rs34988750

Variant names:

• chr13-20189104-C-T
• rs34988750
• NM_004004.6:c.478G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM1 PP2 BP4_Moderate BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:12
• Conservation: PhyloP100: 6.12
• Publications: 25 publications found

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

ENSG00000296095 (HGNC:):

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 0 Cov.: 33

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

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.: 1 Cov.: 33 AF XY: 0.000635 AC XY: 462 AN XY: 727174

African (AFR) AF: 0.00194 AC: 65 AN: 33480

American (AMR) AF: 0.000581 AC: 26 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39694

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53340

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000711 AC: 791 AN: 1111994

Other (OTH) AF: 0.000977 AC: 59 AN: 60394

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.00101 AC XY: 75 AN XY: 74462

African (AFR) AF: 0.00217 AC: 90 AN: 41542

American (AMR) AF: 0.000785 AC: 12 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000772 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000289 AC: 1 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

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	-	5	not specified (5)
-	3	1	Autosomal recessive nonsyndromic hearing loss 1A (4)
-	1	1	Autosomal dominant nonsyndromic hearing loss 3A (2)
-	1	1	Ichthyosis, hystrix-like, with hearing loss (2)
-	1	-	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome (1)
-	-	1	GJB2-related disorder (1)
-	1	-	Nonsyndromic Deafness (1)
-	-	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	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.13	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.77
Sift	Benign	0.060	T
Sift4G	Uncertain	0.053	T
Polyphen		0.97	D
Vest4		0.42
MVP		0.98
MPC		0.20
ClinPred		0.042	T
GERP RS		5.5
Varity_R		0.60
gMVP		0.92
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs34988750; hg19: chr13-20763243;