rs12117176

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.873G>A(p.Pro291Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 1,611,670 control chromosomes in the GnomAD database, including 7,857 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: 33)

Exomes 𝑓: 0.094 ( 7227 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.84

Publications

16 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=0.095).

BP6

Variant 1-40819913-G-A is Benign according to our data. Variant chr1-40819913-G-A is described in ClinVar as Benign. ClinVar VariationId is 45107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.873G>A	p.Pro291Pro	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.873G>A	p.Pro291Pro	synonymous_variant	Exon 6 of 14	1	NM_004700.4	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000509682.6 link	c.873G>A	p.Pro291Pro	synonymous_variant	Exon 6 of 13	5		ENSP00000423756.2	P56696-2
KCNQ4	ENST00000443478.3 link	c.558G>A	p.Pro186Pro	synonymous_variant	Exon 5 of 13	5		ENSP00000406735.3	H0Y6N7
KCNQ4	ENST00000506017.1 link	n.192G>A		non_coding_transcript_exon_variant	Exon 3 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.0805

AC:

12244

AN:

152132

Hom.:

625

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0253

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.0794

Gnomad ASJ

AF:

0.0695

Gnomad EAS

AF:

0.211

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0930

Gnomad OTH

AF:

0.0903

GnomAD2 exomes

AF:

0.106

AC:

26742

AN:

251452

AF XY:

0.107

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.0798

Gnomad ASJ exome

AF:

0.0720

Gnomad EAS exome

AF:

0.225

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.0965

Gnomad OTH exome

AF:

0.103

GnomAD4 exome

AF:

0.0942

AC:

137417

AN:

1459420

Hom.:

7227

Cov.:

AF XY:

0.0951

AC XY:

69033

AN XY:

726114

show subpopulations

African (AFR)

AF:

0.0230

AC:

768

AN:

33458

American (AMR)

AF:

0.0791

AC:

3536

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0754

AC:

1970

AN:

26128

East Asian (EAS)

AF:

0.190

AC:

7519

AN:

39676

South Asian (SAS)

AF:

0.138

AC:

11931

AN:

86158

European-Finnish (FIN)

AF:

0.128

AC:

6851

AN:

53408

Middle Eastern (MID)

AF:

0.0815

AC:

469

AN:

5758

European-Non Finnish (NFE)

AF:

0.0890

AC:

98772

AN:

1109782

Other (OTH)

AF:

0.0928

AC:

5601

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

6121

12241

18362

24482

30603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3596

7192

10788

14384

17980

<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:

0.0805

AC:

12253

AN:

152250

Hom.:

630

Cov.:

AF XY:

0.0834

AC XY:

6207

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0252

AC:

1049

AN:

41570

American (AMR)

AF:

0.0794

AC:

1215

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0695

AC:

241

AN:

3470

East Asian (EAS)

AF:

0.211

AC:

1087

AN:

5158

South Asian (SAS)

AF:

0.138

AC:

666

AN:

4822

European-Finnish (FIN)

AF:

0.127

AC:

1350

AN:

10596

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0930

AC:

6324

AN:

68010

Other (OTH)

AF:

0.0983

AC:

208

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

577

1154

1731

2308

2885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0839

Hom.:

253

Bravo

AF:

0.0738

Asia WGS

AF:

0.164

AC:

568

AN:

3478

EpiCase

AF:

0.0925

EpiControl

AF:

0.0896

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. -

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

Pro291Pro 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 8.7% (611/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs12117176). -

not provided

Benign:2

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

- -

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

-0.70

CADD

Benign

7.5

(source)

DANN

Benign

0.77

PhyloP100

-2.8

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over