NM_004004.6:c.415A>T

Variant names:

• chr13-20189167-T-A
• rs1555341907
• NM_004004.6:c.415A>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_004004.6(GJB2):​c.415A>T​(p.Ser139Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S139N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.97
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_004004.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189166-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44749.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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 13-20189167-T-A is Pathogenic according to our data. Variant chr13-20189167-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 553209.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.415A>T	p.Ser139Cys	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.415A>T	p.Ser139Cys	missense_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.415A>T	p.Ser139Cys	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.415A>T	p.Ser139Cys	missense_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1	n.232-3587A>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 139 of the GJB2 protein (p.Ser139Cys). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser139 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11493200, 12172394, 16380907, 16864573, 17041943, 21465647, 27785406). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. ClinVar contains an entry for this variant (Variation ID: 553209). This missense change has been observed in individual(s) with deafness (PMID: 23751281). This variant is not present in population databases (gnomAD no frequency). -

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1

Aug 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;.;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M;M
PhyloP100		8.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	D;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.79
MutPred		0.65		Loss of MoRF binding (P = 0.0903);Loss of MoRF binding (P = 0.0903);Loss of MoRF binding (P = 0.0903);
MVP		0.98
MPC		0.28
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.93
Mutation Taster		=3/97	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: rs1555341907; hg19: chr13-20763306;