rs398123815

Positions:

• chr13-20189475-A-AGGATCATAATGCGAAAAATGAAGAGGACGG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_004004.6(GJB2):​c.106_107insCCGTCCTCTTCATTTTTCGCATTATGATCC​(p.Ile35_Leu36insProValLeuPheIlePheArgIleMetIle) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.01

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a transmembrane_region Helical (size 19) in uniprot entity CXB2_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_004004.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004004.6.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.106_107insCCGTCCTCTTCATTTTTCGCATTATGATCC	p.Ile35_Leu36insProValLeuPheIlePheArgIleMetIle	inframe_insertion	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.106_107insCCGTCCTCTTCATTTTTCGCATTATGATCC	p.Ile35_Leu36insProValLeuPheIlePheArgIleMetIle	inframe_insertion	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.106_107insCCGTCCTCTTCATTTTTCGCATTATGATCC	p.Ile35_Leu36insProValLeuPheIlePheArgIleMetIle	inframe_insertion	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.106_107insCCGTCCTCTTCATTTTTCGCATTATGATCC	p.Ile35_Leu36insProValLeuPheIlePheArgIleMetIle	inframe_insertion	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Eurofins Ntd Llc (ga)

Nov 21, 2012

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123815; hg19: chr13-20763614;