rs2361660

Variant names:

• chr1-40818694-G-C
• rs2361660
• NM_004700.4:c.708+14G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004700.4(KCNQ4):​c.708+14G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,581,178 control chromosomes in the GnomAD database, including 384,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33430 hom., cov: 32)
  • Exomes 𝑓: 0.70 (350707 hom.)
• Consequence: KCNQ4 NM_004700.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0700
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-40818694-G-C is Benign according to our data. Variant chr1-40818694-G-C is described in ClinVar as Benign. ClinVar VariationId is 45104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.708+14G>C		intron_variant	Intron 4 of 13	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.708+14G>C		intron_variant	Intron 4 of 13	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.708+14G>C		intron_variant	Intron 4 of 12	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.393+14G>C		intron_variant	Intron 3 of 12	5		ENSP00000406735.3

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99842 AN: 151884 Hom.: 33414 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.661

GnomAD2 exomes AF: 0.643 AC: 124402 AN: 193618 AF XY: 0.647

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.720

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.697 AC: 995938 AN: 1429174 Hom.: 350707 Cov.: 50 AF XY: 0.694 AC XY: 492785 AN XY: 709718

African (AFR) AF: 0.591 AC: 19408 AN: 32818

American (AMR) AF: 0.525 AC: 21486 AN: 40940

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 17092 AN: 25690

East Asian (EAS) AF: 0.415 AC: 15793 AN: 38044

South Asian (SAS) AF: 0.575 AC: 48057 AN: 83536

European-Finnish (FIN) AF: 0.734 AC: 31870 AN: 43428

Middle Eastern (MID) AF: 0.685 AC: 3280 AN: 4788

European-Non Finnish (NFE) AF: 0.726 AC: 798732 AN: 1100656

Other (OTH) AF: 0.679 AC: 40220 AN: 59274

GnomAD4 genome AF: 0.657 AC: 99896 AN: 152004 Hom.: 33430 Cov.: 32 AF XY: 0.653 AC XY: 48467 AN XY: 74272

African (AFR) AF: 0.592 AC: 24571 AN: 41490

American (AMR) AF: 0.555 AC: 8475 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2321 AN: 3470

East Asian (EAS) AF: 0.454 AC: 2314 AN: 5096

South Asian (SAS) AF: 0.569 AC: 2741 AN: 4816

European-Finnish (FIN) AF: 0.716 AC: 7571 AN: 10578

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49605 AN: 67958

Other (OTH) AF: 0.664 AC: 1402 AN: 2112

Alfa AF: 0.703 Hom.: 6966

Bravo AF: 0.642

Asia WGS AF: 0.540 AC: 1880 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

708+14G>C in Intron 04 of KCNQ4: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence and has been identified in 39.7% (1449/3654) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2361660). -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 2A Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.36
PhyloP100		0.070
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2361660; hg19: chr1-41284366; COSMIC: COSV61273257; COSMIC: COSV61273257;