rs397516868

chr13-20192805-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_004004.6(GJB2):c.-45C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 153,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 0 hom. )

Consequence

GJB2
NM_004004.6 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 0.712

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 13-20192805-G-T is Benign according to our data. Variant chr13-20192805-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 44720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20192805-G-T is described in Lovd as [Likely_benign]. Variant chr13-20192805-G-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.-45C>A		5_prime_UTR_variant	1/2	ENST00000382848.5
GJB2	XM_011535049.3 linkuse as main transcript	c.-867C>A		5_prime_UTR_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.-45C>A		5_prime_UTR_variant	1/2	1	NM_004004.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00236

AC:

359

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00440

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.00329

AC:

AN:

1214

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

AN XY:

742

show subpopulations

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:

0.00778

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152200

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00440

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00249

Hom.:

Bravo

AF:

0.00218

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2017	c.-45C>A in Exon 1 of GJB2: This variant has been identified in 0.4%(58/14946) o f European chromosomes by the Genome Aggregation Database (gnomAD; http://gnoma d.broadinstitute.org; dbSNP rs397516868). Expression studies showed presence of the expressed GJB2 gene (Wilch 2006). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2021	Variant summary: GJB2 c.-45C>A is located in the untranslated mRNA region upstream of the initiation codon. One in silico tool predicts a benign outcome for this variant. The variant allele was found at a frequency of 0.0024 in 31410 control chromosomes, predominantly at a frequency of 0.0039 within the Non-Finnish European subpopulation in the gnomAD database (genomes). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss phenotype (0.00034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.-45C>A, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss but was also found in controls (Matos_2011). In addition, multiple publications classify the variant as polymorphism (Wilch_2006, Bliznets_2012, Beck_2014), which is supported by the evidence that the variant was observed in trans with a pathogenic allele in an unaffected individual, suggesting a lack of segregation with disease. An allele-based expression analysis showed presence of the expressed GJB2 gene (Wilch_2006) demonstrating no damaging effect of this variant. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 10, 2021	- -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:1

Pathogenic, flagged submission

clinical testing

Integrating Genomics into Medicine, Frazer Institute, University Of Queensland

Jun 02, 2023

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

8.9

Dann

Benign

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over