13-20189202-C-T

Variant names:

• chr13-20189202-C-T
• rs111033196
• NM_004004.6:c.380G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004004.6(GJB2):​c.380G>A​(p.Arg127His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 1,613,694 control chromosomes in the GnomAD database, including 573 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127L) has been classified as Likely pathogenic. The gene GJB2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0048 (42 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (531 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:17
• Conservation: PhyloP100: 0.669
• Publications: 110 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

Specifications for GJB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_004004.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189202-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195204.
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018435419).
• BP6: Variant 13-20189202-C-T is Benign according to our data. Variant chr13-20189202-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

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.380G>A	p.Arg127His	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.380G>A	p.Arg127His	missense	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.380G>A	p.Arg127His	missense	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.380G>A	p.Arg127His	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 730 AN: 152044 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.0139 AC: 3478 AN: 250364 AF XY: 0.0175

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.000282

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00792 AC: 11569 AN: 1461532 Hom.: 531 Cov.: 33 AF XY: 0.0103 AC XY: 7506 AN XY: 727068

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00451 AC: 118 AN: 26136

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39700

South Asian (SAS) AF: 0.0917 AC: 7910 AN: 86258

European-Finnish (FIN) AF: 0.000377 AC: 20 AN: 53070

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.00262 AC: 2912 AN: 1112004

Other (OTH) AF: 0.00888 AC: 536 AN: 60392

GnomAD4 genome AF: 0.00480 AC: 730 AN: 152162 Hom.: 42 Cov.: 33 AF XY: 0.00644 AC XY: 479 AN XY: 74402

African (AFR) AF: 0.000603 AC: 25 AN: 41492

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5162

South Asian (SAS) AF: 0.106 AC: 512 AN: 4814

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 67986

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00287 Hom.: 17

Bravo AF: 0.00204

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.0153 AC: 1863

Asia WGS AF: 0.0420 AC: 149 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	3	Autosomal recessive nonsyndromic hearing loss 1A (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 3A (1)
-	-	1	Ichthyosis, hystrix-like, with hearing loss (1)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	1	-	Progressive sensorineural hearing impairment (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0018	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.3	L
PhyloP100		0.67
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.39
Sift	Benign	0.21	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.023
MPC		0.044
ClinPred		0.014	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.74
Mutation Taster		=88/12	polymorphism (auto)

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: rs111033196; hg19: chr13-20763341; COSMIC: COSV67010868;