chr13-20189284-G-A

Variant names:

• chr13-20189284-G-A
• rs143343083
• NM_004004.6:c.298C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_004004.6(GJB2):​c.298C>T​(p.His100Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000919427: "A functional study showed lack of hemichannel permeability/conductivity associated with this variant (Kim_2016)."; SCV000603836: "The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis." Kim HR et al. Hum Genet. 2016 Mar;135(3):287-98.; SCV000937718: Experimental studies have shown that this missense change affects GJB2 function (PMID:26749107).; SCV001825360: Published functional studies demonstrate a damaging effect on hemichannel permeability (Kim et al., 2016); SCV005361414: "In vitro studies found this variant is nonfunctional as a homotypic gap junction." PMID:26749107". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H100L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 8.06
• Publications: 12 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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, G2P, Genomics England PanelApp
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• syndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000919427: "A functional study showed lack of hemichannel permeability/conductivity associated with this variant (Kim_2016)."; SCV000603836: "The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis." Kim HR et al. Hum Genet. 2016 Mar;135(3):287-98.; SCV000937718: Experimental studies have shown that this missense change affects GJB2 function (PMID: 26749107).; SCV001825360: Published functional studies demonstrate a damaging effect on hemichannel permeability (Kim et al., 2016); SCV005361414: "In vitro studies found this variant is nonfunctional as a homotypic gap junction." PMID:26749107
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_004004.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189283-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 633242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 dominant nonsyndromic hearing loss 3A, ichthyosis, hystrix-like, with hearing loss, autosomal recessive nonsyndromic hearing loss 1A, nonsyndromic genetic hearing loss, palmoplantar keratoderma-deafness syndrome, keratoderma hereditarium mutilans, Bart-Pumphrey syndrome, KID syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, autosomal dominant nonsyndromic hearing loss, hearing loss, autosomal recessive, syndromic genetic hearing loss.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 13-20189284-G-A is Pathogenic according to our data. Variant chr13-20189284-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 158607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.298C>T	p.His100Tyr	missense	Exon 2 of 2	NP_003995.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.298C>T	p.His100Tyr	missense	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.298C>T	p.His100Tyr	missense	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.298C>T	p.His100Tyr	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152092 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250900 AF XY: 0.00

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461580 Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1112010

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152092 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74286

African (AFR) AF: 0.0000483 AC: 2 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000525 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
4	-	-	Autosomal recessive nonsyndromic hearing loss 1A (4)
1	-	-	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A (1)
1	-	-	GJB2-related disorder (1)
1	-	-	Hearing impairment (1)
1	-	-	Hearing loss (1)
1	-	-	nonsyndromic sensorineural hearing loss (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.80
Sift	Benign	0.053	T
Sift4G	Uncertain	0.050	T
Polyphen		0.99	D
Vest4		0.78
MVP		0.97
MPC		0.16
ClinPred		0.94	D
GERP RS		5.3
PromoterAI		0.037	Neutral
Varity_R		0.77
gMVP		0.89
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs143343083; hg19: chr13-20763423;