rs4660468

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000347132.10(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
ENST00000347132.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -4.41

Variant links:

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]

KCNQ4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
KCNQ4	NM_004700.4 linkuse as main transcript	c.777T>C	p.Ala259=	synonymous_variant	5/14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10 linkuse as main transcript	c.777T>C	p.Ala259=	synonymous_variant	5/14	1	NM_004700.4	ENSP00000262916	P2	P56696-1
KCNQ4	ENST00000509682.6 linkuse as main transcript	c.777T>C	p.Ala259=	synonymous_variant	5/13	5		ENSP00000423756	A1	P56696-2
KCNQ4	ENST00000443478.3 linkuse as main transcript	c.465T>C	p.Ala155=	synonymous_variant	4/13	5		ENSP00000406735
KCNQ4	ENST00000506017.1 linkuse as main transcript	n.96T>C		non_coding_transcript_exon_variant	2/11	2

Frequencies

GnomAD3 genomes

AF:

0.652

AC:

98868

AN:

151664

Hom.:

32894

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.694

AC XY:

504564

AN XY:

727158

show subpopulations

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.:

AF XY:

0.646

AC XY:

47913

AN XY:

74178

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	-	- -
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	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. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal dominant nonsyndromic hearing loss 2A

Benign:2

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

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

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