rs4660468

chr1-40819415-T-Cchr1-40819415-T-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.777T>C(p.Ala259=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 1,613,444 control chromosomes in the GnomAD database, including 391,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.65 (32904 hom., cov: 30)
  • Exomes 𝑓: 0.70 (358645 hom.)
• Consequence: KCNQ4 NM_004700.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.41

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=-0.73).
• BP6: Variant 1-40819415-T-C is Benign according to our data. Variant chr1-40819415-T-C is described in ClinVar as [Benign]. Clinvar id is 45105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40819415-T-C is described in Lovd as [Benign]. Variant chr1-40819415-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.777T>C	p.Ala259=	synonymous_variant	5/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.777T>C	p.Ala259=	synonymous_variant	5/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.777T>C	p.Ala259=	synonymous_variant	5/13	5		A1
KCNQ4	ENST00000443478.3	c.465T>C	p.Ala155=	synonymous_variant	4/13	5
KCNQ4	ENST00000506017.1	n.96T>C		non_coding_transcript_exon_variant	2/11	2

Frequencies

GnomAD3 genomes AF: 0.652 AC: 98868 AN: 151664 Hom.: 32894 Cov.: 30

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.653

GnomAD3 exomes AF: 0.646 AC: 162346 AN: 251388 Hom.: 53818 AF XY: 0.651 AC XY: 88445 AN XY: 135876

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.449

Gnomad SAS exome AF: 0.579

Gnomad FIN exome AF: 0.719

Gnomad NFE exome AF: 0.729

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.696 AC: 1017384 AN: 1461662 Hom.: 358645 Cov.: 56 AF XY: 0.694 AC XY: 504564 AN XY: 727158

Gnomad4 AFR exome AF: 0.573

Gnomad4 AMR exome AF: 0.522

Gnomad4 ASJ exome AF: 0.662

Gnomad4 EAS exome AF: 0.386

Gnomad4 SAS exome AF: 0.580

Gnomad4 FIN exome AF: 0.731

Gnomad4 NFE exome AF: 0.727

Gnomad4 OTH exome AF: 0.677

GnomAD4 genome AF: 0.652 AC: 98918 AN: 151782 Hom.: 32904 Cov.: 30 AF XY: 0.646 AC XY: 47913 AN XY: 74178

Gnomad4 AFR AF: 0.573

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.665

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.573

Gnomad4 FIN AF: 0.715

Gnomad4 NFE AF: 0.731

Gnomad4 OTH AF: 0.657

Alfa AF: 0.708 Hom.: 90794

Bravo AF: 0.636

Asia WGS AF: 0.527 AC: 1836 AN: 3478

EpiCase AF: 0.733

EpiControl AF: 0.728

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala259Ala in Exon 05 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 42.4% (1584/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs4660468). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal dominant nonsyndromic hearing loss 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	-0.73
Cadd	Benign	3.8
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4660468; hg19: chr1-41285087; COSMIC: COSV61273267;