rs9578260

Variant names:

• chr13-20189615-G-A
• rs9578260
• NM_004004.6:c.-22-12C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-20189615-G-A
• chr13-20189615-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004004.6(GJB2):​c.-22-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,576,854 control chromosomes in the GnomAD database, including 2,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (1190 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (1015 hom.)
• Consequence: GJB2 NM_004004.6 intron
• Scores: Splicing: ADA: 0.00001612
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.77
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• syndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 13-20189615-G-A is Benign according to our data. Variant chr13-20189615-G-A is described in ClinVar as Benign. ClinVar VariationId is 44717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.-22-12C>T		intron	N/A	NP_003995.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.-22-12C>T		intron	N/A	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10419 AN: 152046 Hom.: 1177 Cov.: 33

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0177 AC: 4413 AN: 248752 AF XY: 0.0131

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000639

Gnomad OTH exome AF: 0.00964

GnomAD4 exome AF: 0.00708 AC: 10084 AN: 1424690 Hom.: 1015 Cov.: 26 AF XY: 0.00600 AC XY: 4267 AN XY: 710890

African (AFR) AF: 0.240 AC: 7904 AN: 32870

American (AMR) AF: 0.0136 AC: 606 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00112 AC: 29 AN: 25912

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39528

South Asian (SAS) AF: 0.000433 AC: 37 AN: 85496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.0112 AC: 57 AN: 5076

European-Non Finnish (NFE) AF: 0.000439 AC: 474 AN: 1078654

Other (OTH) AF: 0.0165 AC: 974 AN: 59082

GnomAD4 genome AF: 0.0688 AC: 10473 AN: 152164 Hom.: 1190 Cov.: 33 AF XY: 0.0662 AC XY: 4925 AN XY: 74426

African (AFR) AF: 0.239 AC: 9897 AN: 41446

American (AMR) AF: 0.0274 AC: 419 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68014

Other (OTH) AF: 0.0455 AC: 96 AN: 2112

Alfa AF: 0.0565 Hom.: 279

Bravo AF: 0.0786

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 1A (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 3A (1)
-	-	1	Ichthyosis, hystrix-like, with hearing loss (1)
-	-	1	Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.61
PhyloP100		1.8
PromoterAI		0.0020	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs9578260; hg19: chr13-20763754;