rs12143503

chr1-40819919-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004700.4(KCNQ4):c.879A>G(p.Thr293=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.093 in 1,612,286 control chromosomes in the GnomAD database, including 7,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (630 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7245 hom.)
• Consequence: KCNQ4 NM_004700.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.56

Genes affected

KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-40819919-A-G is Benign according to our data. Variant chr1-40819919-A-G is described in ClinVar as [Benign]. Clinvar id is 45108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40819919-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.879A>G	p.Thr293=	synonymous_variant	6/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.879A>G	p.Thr293=	synonymous_variant	6/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.879A>G	p.Thr293=	synonymous_variant	6/13	5		A1
KCNQ4	ENST00000443478.3	c.567A>G	p.Thr189=	synonymous_variant	5/13	5
KCNQ4	ENST00000506017.1	n.198A>G		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12226 AN: 152114 Hom.: 625 Cov.: 32

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.0694

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0930

Gnomad OTH AF: 0.0903

GnomAD3 exomes AF: 0.106 AC: 26767 AN: 251438 Hom.: 1699 AF XY: 0.108 AC XY: 14622 AN XY: 135888

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.0796

Gnomad ASJ exome AF: 0.0720

Gnomad EAS exome AF: 0.227

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0965

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0944 AC: 137787 AN: 1460054 Hom.: 7245 Cov.: 33 AF XY: 0.0953 AC XY: 69199 AN XY: 726390

Gnomad4 AFR exome AF: 0.0223

Gnomad4 AMR exome AF: 0.0789

Gnomad4 ASJ exome AF: 0.0754

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.0892

Gnomad4 OTH exome AF: 0.0929

GnomAD4 genome AF: 0.0804 AC: 12233 AN: 152232 Hom.: 630 Cov.: 32 AF XY: 0.0833 AC XY: 6198 AN XY: 74434

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.0795

Gnomad4 ASJ AF: 0.0694

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.0929

Gnomad4 OTH AF: 0.0984

Alfa AF: 0.0848 Hom.: 304

Bravo AF: 0.0738

Asia WGS AF: 0.164 AC: 568 AN: 3478

EpiCase AF: 0.0924

EpiControl AF: 0.0898

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr293Thr in Exon 06 of KCNQ4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 8.3% (580/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs12143503). -

Autosomal dominant nonsyndromic hearing loss 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.0
Dann	Benign	0.50

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

Other links and lift over

dbSNP: rs12143503; hg19: chr1-41285591; COSMIC: COSV61272035;