rs1555341782

chr13-20188908-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004004.6(GJB2):c.674C>T(p.Pro225Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. P225P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 5.50

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 218 pathogenic changes around while only 32 benign (87%) in NM_004004.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.674C>T	p.Pro225Leu	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.674C>T	p.Pro225Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.674C>T	p.Pro225Leu	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.674C>T	p.Pro225Leu	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 19, 2017

- -

Nonsyndromic genetic hearing loss Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 20, 2018

The p.Pro225Leu variant in GJB2 is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). This variant has been detected in 1 patient with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3; PMID:21112098). In summary, this variant meets criteria to be classified as a variant of uncertain clinical significance for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	-0.023
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	0.51	N;N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		0.27	B;B;B
Vest4		0.22
MutPred		0.34		Gain of stability (P = 0.0053);Gain of stability (P = 0.0053);Gain of stability (P = 0.0053);
MVP		0.95
MPC		0.039
ClinPred		0.73	D
GERP RS		5.7
Varity_R		0.096
gMVP		0.69

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: rs1555341782; hg19: chr13-20763047;