rs12143503

Variant names:

Variant summary

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

The NM_004700.4(KCNQ4):c.879A>G(p.Thr293Thr) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.56

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=-0.83).

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 rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.879A>G	p.Thr293Thr	synonymous_variant	Exon 6 of 14	ENST00000347132.10	NP_004691.2	P56696-1B3KQH8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ4	ENST00000347132.10 link	c.879A>G	p.Thr293Thr	synonymous_variant	Exon 6 of 14	1	NM_004700.4	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000509682.6 link	c.879A>G	p.Thr293Thr	synonymous_variant	Exon 6 of 13	5		ENSP00000423756.2	P56696-2
KCNQ4	ENST00000443478.3 link	c.564A>G	p.Thr188Thr	synonymous_variant	Exon 5 of 13	5		ENSP00000406735.3	H0Y6N7
KCNQ4	ENST00000506017.1 link	n.198A>G		non_coding_transcript_exon_variant	Exon 3 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.0804

AC:

12226

AN:

152114

Hom.:

625

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0953

AC XY:

69199

AN XY:

726390

show subpopulations

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.:

AF XY:

0.0833

AC XY:

6198

AN XY:

74434

show subpopulations

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nonsyndromic hearing loss 2A

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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