rs55964611

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004700.4(KCNQ4):c.1665G>A(p.Pro555Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,613,944 control chromosomes in the GnomAD database, including 1,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 122 hom., cov: 31)

Exomes 𝑓: 0.037 ( 1111 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.63

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 1-40835018-G-A is Benign according to our data. Variant chr1-40835018-G-A is described in ClinVar as [Benign]. Clinvar id is 45103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40835018-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.63 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0315 (4805/152320) while in subpopulation NFE AF= 0.0453 (3081/68026). AF 95% confidence interval is 0.044. There are 122 homozygotes in gnomad4. There are 2309 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4805 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.1665G>A	p.Pro555Pro	synonymous_variant	Exon 12 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.1665G>A	p.Pro555Pro	synonymous_variant	Exon 12 of 14	1	NM_004700.4	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000509682.6 link	c.1503G>A	p.Pro501Pro	synonymous_variant	Exon 11 of 13	5		ENSP00000423756.2	P56696-2
KCNQ4	ENST00000443478.3 link	c.1245G>A	p.Pro415Pro	synonymous_variant	Exon 11 of 13	5		ENSP00000406735.3	H0Y6N7
KCNQ4	ENST00000506017.1 link	n.984G>A		non_coding_transcript_exon_variant	Exon 9 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.0315

AC:

4801

AN:

152202

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00827

Gnomad FIN

AF:

0.0624

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0453

Gnomad OTH

AF:

0.0287

GnomAD3 exomes

AF:

0.0301

AC:

7569

AN:

251452

Hom.:

181

AF XY:

0.0304

AC XY:

4131

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.0154

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00921

Gnomad FIN exome

AF:

0.0572

Gnomad NFE exome

AF:

0.0441

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0371

AC:

54282

AN:

1461624

Hom.:

1111

Cov.:

AF XY:

0.0364

AC XY:

26464

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

Gnomad4 AMR exome

AF:

0.0157

Gnomad4 ASJ exome

AF:

0.0167

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00914

Gnomad4 FIN exome

AF:

0.0578

Gnomad4 NFE exome

AF:

0.0421

Gnomad4 OTH exome

AF:

0.0324

GnomAD4 genome

AF:

0.0315

AC:

4805

AN:

152320

Hom.:

122

Cov.:

AF XY:

0.0310

AC XY:

2309

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.0188

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00828

Gnomad4 FIN

AF:

0.0624

Gnomad4 NFE

AF:

0.0453

Gnomad4 OTH

AF:

0.0284

Alfa

AF:

0.0312

Hom.:

Bravo

AF:

0.0283

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0403

EpiControl

AF:

0.0406

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Sep 08, 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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro555Pro in Exon 12 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 3.9% (276/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs55964611). -

not provided

Benign:3

Nov 09, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 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

0.20

DANN

Benign

0.77

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