rs786204734

Positions:

• chr13-20192783-C-A
• chr13-20192783-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The ENST00000382848.5(GJB2):​c.-23G>T variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000457 in 153,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: GJB2 ENST00000382848.5 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.9942
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 0.633

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 1 ACMG points.

• PP5: Variant 13-20192783-C-A is Pathogenic according to our data. Variant chr13-20192783-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 189155.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.-23G>T		splice_region_variant, 5_prime_UTR_variant	1/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.-845G>T		5_prime_UTR_variant	1/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.-23G>T		splice_region_variant, 5_prime_UTR_variant	1/2	1	NM_004004.6	ENSP00000372299	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000880 AC: 1 AN: 1136 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 712

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: 0.00185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 26, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0212 - This variant affects the last nucleotide of GJB2 exon 1 which is located in the non-coding 5'UTR region. However, it has also been described as a non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (6 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same splice region is present in gnomAD (v3) at a frequency of 0.00002 (3 heterozygotes, 0 homozygotes). (SB) 0508 - In silico predictions for abnormal splicing are inconclusive. Abnormal splicing has been predicted by only one of two in silico tools and the nucleotide is poorly conserved. (I) 0705 - No comparable splice region variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported to be compound heterozygous in one individual with non-syndromic sensorineural hearing loss and has been classified as likely pathogenic or pathogenic by three clinical diagnostic laboratories (ClinVar, PMID: 18941476). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jun 02, 2017

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 15, 2023

Variant summary: GJB2 c.-23G>T is located in the untranslated mRNA region upstream of the initiation codon. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. One predict the variant abolishes a 5' splicing donor site. Three predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 31290 control chromosomes. c.-23G>T has been reported in the literature in compound heterozygosity with another variant in at least one individual affected with Non-Syndromic Hearing Loss (e.g. Mani_2009). These data do not allow any conclusion about variant significance. However, several other variants located within this splicing region have previously been reported as pathogenic by our laboratory (e.g. c.-22-2A>C and c.-23+1G>A) and this variant (c.-23G>T) has been reported as a "pathogenic" mutation by multiple subsequent publications (e.g. Kim_2016, Han_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22567369, 18941476, 27057829, 30733538, 29311818, No_PMID). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 26, 2022

The c.-23G>T variant in GJB2 has been previously reported in 2 individuals with hearing loss who were compound heterozygous with another pathogenic variant in GJB2 (Mani 2009 PMID: 18941476, Tilton 2014 [conference abstract], LMM unpublished data), and was absent in 192 control chromosomes (Mani 2009 PMID: 18941476). This variant has been identified in 6/4836 (0.1%) South Asian chromosomes chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant is located in the last base of the exon, which is part of the 5’ splice region, and computational tools suggest an impact to splicing. In summary, although additional studies are required to fully establish its clinical significance, the c.-23G>T variant is likely pathogenic. ACMG/AMP criteria applied: PM3_Strong, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.12		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: rs786204734; hg19: chr13-20766922;