NM_004004.6:c.-23+12G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_004004.6(GJB2):c.-23+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 152,182 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GJB2
NM_004004.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.25

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 13-20192771-C-T is Benign according to our data. Variant chr13-20192771-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20192771-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00543 (827/152182) while in subpopulation AFR AF= 0.0189 (784/41550). AF 95% confidence interval is 0.0178. There are 10 homozygotes in gnomad4. There are 413 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR,Digenic geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.-23+12G>A		intron_variant	Intron 1 of 1	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.-833G>A		5_prime_UTR_variant	Exon 1 of 2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 link	c.-23+12G>A		intron_variant	Intron 1 of 1	1	NM_004004.6	ENSP00000372299.4		P29033

Frequencies

GnomAD3 genomes

AF:

0.00542

AC:

824

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00382

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

468

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00543

AC:

827

AN:

152182

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

413

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0189

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000768

Hom.:

Bravo

AF:

0.00602

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 27, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.-23+12G>A in intron 1 of GJB2: This variant is not expected to have clinical s ignificance because it has been identified in 1.9% (165/8692) of African chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs397516866). -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GJB2 c.-23+12G>A variant involves the alteration of a non-conserved nucleotide in the first intron of the gene. One in silico tool predicts a benign outcome for this variant and 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 167/30820 control chromosomes (2 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.018983 (165/8692). This frequency is about 56 times the estimated maximal expected allele frequency of a dominant pathogenic GJB2 variant (0.0003376), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In a recessive inheritance model, this frequency does not exceed the maximal expected frequency for a recessive pathogenic GJB2 variant (0.02598). However, the presence of two normal homozygous individuals in the gnomAD database support a benign impact of this variant in either inheritance model. The variant has been found in at least 7 hearing loss patients. However, in 6 reported patients, this variant was found in heterozygous state, suggesting that this variant might not explain the phenotype in the patients because hearing loss is predominantly a recessive disorder, and the high allele frequency in African controls suggests that this variant is not a dominant hearing loss causative variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign or benign. Taken together, this variant is classified as benign. -

not provided

Benign:1

Nov 06, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.6

DANN

Benign

0.97

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