NM_004700.4:c.841T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004700.4(KCNQ4):c.841T>C(p.Leu281Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,613,114 control chromosomes in the GnomAD database, including 1,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 156 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1635 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.26

Publications

11 publications found

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 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

KCNQ4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.141).

BP6

Variant 1-40819881-T-C is Benign according to our data. Variant chr1-40819881-T-C is described in ClinVar as Benign. ClinVar VariationId is 45106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004700.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	NM_004700.4	MANE Select	c.841T>C	p.Leu281Leu	synonymous	Exon 6 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.841T>C	p.Leu281Leu	synonymous	Exon 6 of 13	NP_751895.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.841T>C	p.Leu281Leu	synonymous	Exon 6 of 14	ENSP00000262916.6
KCNQ4	ENST00000509682.6	TSL:5	c.841T>C	p.Leu281Leu	synonymous	Exon 6 of 13	ENSP00000423756.2
KCNQ4	ENST00000443478.3	TSL:5	c.526T>C	p.Leu176Leu	synonymous	Exon 5 of 13	ENSP00000406735.3

Frequencies

GnomAD3 genomes

AF:

0.0379

AC:

5766

AN:

152166

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.0538

Gnomad ASJ

AF:

0.0732

Gnomad EAS

AF:

0.0524

Gnomad SAS

AF:

0.0335

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0645

GnomAD2 exomes

AF:

0.0400

AC:

10066

AN:

251490

AF XY:

0.0418

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.0338

Gnomad ASJ exome

AF:

0.0670

Gnomad EAS exome

AF:

0.0555

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.0472

Gnomad OTH exome

AF:

0.0484

GnomAD4 exome

AF:

0.0452

AC:

66036

AN:

1460830

Hom.:

1635

Cov.:

AF XY:

0.0451

AC XY:

32772

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.0142

AC:

476

AN:

33458

American (AMR)

AF:

0.0352

AC:

1573

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0670

AC:

1751

AN:

26126

East Asian (EAS)

AF:

0.0490

AC:

1946

AN:

39692

South Asian (SAS)

AF:

0.0337

AC:

2907

AN:

86230

European-Finnish (FIN)

AF:

0.0169

AC:

901

AN:

53418

Middle Eastern (MID)

AF:

0.0903

AC:

521

AN:

5768

European-Non Finnish (NFE)

AF:

0.0478

AC:

53060

AN:

1111060

Other (OTH)

AF:

0.0481

AC:

2901

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

3194

6388

9582

12776

15970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1998

3996

5994

7992

9990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0378

AC:

5755

AN:

152284

Hom.:

156

Cov.:

AF XY:

0.0366

AC XY:

2725

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0146

AC:

605

AN:

41556

American (AMR)

AF:

0.0537

AC:

821

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0732

AC:

254

AN:

3472

East Asian (EAS)

AF:

0.0516

AC:

267

AN:

5176

South Asian (SAS)

AF:

0.0340

AC:

164

AN:

4826

European-Finnish (FIN)

AF:

0.0140

AC:

149

AN:

10624

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0478

AC:

3252

AN:

68016

Other (OTH)

AF:

0.0629

AC:

133

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

300

600

900

1200

1500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0418

Hom.:

Bravo

AF:

0.0403

Asia WGS

AF:

0.0430

AC:

149

AN:

3478

EpiCase

AF:

0.0576

EpiControl

AF:

0.0549

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 09, 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

Leu281Leu 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 4.7% (333/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs55737429).

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.5

(source)

DANN

Benign

0.50

PhyloP100

2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over