rs397516876

Positions:

• chr13-20189170-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP6_Very_Strong

The NM_004004.6(GJB2):​c.412A>G​(p.Ser138Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.219

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004004.6
• BP6: Variant 13-20189170-T-C is Benign according to our data. Variant chr13-20189170-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 44748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.412A>G	p.Ser138Gly	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.412A>G	p.Ser138Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.412A>G	p.Ser138Gly	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.412A>G	p.Ser138Gly	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250882 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461772 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 18, 2011

Ser138Gly in exon 2 of GJB2: This variant has been reported in the literature af ter identification in one patient with hearing loss; however, a variant on the s econd allele was not found (Picciotti 2009). Computational analyses (PolyPhen, S IFT, AlignGVGD) do not suggest a high likelihood of clinical significance primar ily based upon a lack of evolutionary conservation. Of note, cow and sheep have a glycine at this position despite high nearby amino acid conservation. In summa ry this data suggests that this variant is likely benign. -

Autosomal recessive nonsyndromic hearing loss 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;D;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.76	.;.;T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	0.84	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.2	N;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.039	D;D;.
Sift4G	Benign	0.12	T;T;.
Polyphen		0.046	B;B;B
Vest4		0.70
MutPred		0.86		Loss of catalytic residue at S138 (P = 0.0523);Loss of catalytic residue at S138 (P = 0.0523);Loss of catalytic residue at S138 (P = 0.0523);
MVP		0.86
MPC		0.037
ClinPred		0.22	T
GERP RS		4.2
Varity_R		0.29
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs397516876; hg19: chr13-20763309;