1-40819415-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004700.4(KCNQ4):c.777T>C(p.Ala259Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 1,613,444 control chromosomes in the GnomAD database, including 391,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.65 ( 32904 hom., cov: 30)

Exomes 𝑓: 0.70 ( 358645 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.41

Publications

29 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
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 1-40819415-T-C is Benign according to our data. Variant chr1-40819415-T-C is described in ClinVar as Benign. ClinVar VariationId is 45105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.41 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.726 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	NM_004700.4	MANE Select	c.777T>C	p.Ala259Ala	synonymous	Exon 5 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.777T>C	p.Ala259Ala	synonymous	Exon 5 of 13	NP_751895.1	P56696-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.777T>C	p.Ala259Ala	synonymous	Exon 5 of 14	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000967337.1		c.777T>C	p.Ala259Ala	synonymous	Exon 5 of 14	ENSP00000637396.1
KCNQ4	ENST00000967338.1		c.777T>C	p.Ala259Ala	synonymous	Exon 5 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes

AF:

0.652

AC:

98868

AN:

151664

Hom.:

32894

Cov.:

show subpopulations

Gnomad AFR

AF:

0.574

Gnomad AMI

AF:

0.761

Gnomad AMR

AF:

0.555

Gnomad ASJ

AF:

0.665

Gnomad EAS

AF:

0.433

Gnomad SAS

AF:

0.573

Gnomad FIN

AF:

0.715

Gnomad MID

AF:

0.696

Gnomad NFE

AF:

0.731

Gnomad OTH

AF:

0.653

GnomAD2 exomes

AF:

0.646

AC:

162346

AN:

251388

AF XY:

0.651

show subpopulations

Gnomad AFR exome

AF:

0.568

Gnomad AMR exome

AF:

0.515

Gnomad ASJ exome

AF:

0.666

Gnomad EAS exome

AF:

0.449

Gnomad FIN exome

AF:

0.719

Gnomad NFE exome

AF:

0.729

Gnomad OTH exome

AF:

0.676

GnomAD4 exome

AF:

0.696

AC:

1017384

AN:

1461662

Hom.:

358645

Cov.:

AF XY:

0.694

AC XY:

504564

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.573

AC:

19175

AN:

33478

American (AMR)

AF:

0.522

AC:

23322

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.662

AC:

17301

AN:

26130

East Asian (EAS)

AF:

0.386

AC:

15335

AN:

39700

South Asian (SAS)

AF:

0.580

AC:

50024

AN:

86256

European-Finnish (FIN)

AF:

0.731

AC:

38968

AN:

53302

Middle Eastern (MID)

AF:

0.690

AC:

3977

AN:

5766

European-Non Finnish (NFE)

AF:

0.727

AC:

808414

AN:

1111928

Other (OTH)

AF:

0.677

AC:

40868

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

17974

35947

53921

71894

89868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19838

39676

59514

79352

99190

<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:

0.652

AC:

98918

AN:

151782

Hom.:

32904

Cov.:

AF XY:

0.646

AC XY:

47913

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.573

AC:

23710

AN:

41356

American (AMR)

AF:

0.554

AC:

8462

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.665

AC:

2305

AN:

3468

East Asian (EAS)

AF:

0.432

AC:

2216

AN:

5126

South Asian (SAS)

AF:

0.573

AC:

2740

AN:

4778

European-Finnish (FIN)

AF:

0.715

AC:

7544

AN:

10556

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.731

AC:

49658

AN:

67902

Other (OTH)

AF:

0.657

AC:

1384

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1659

3319

4978

6638

8297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.699

Hom.:

177059

Bravo

AF:

0.636

Asia WGS

AF:

0.527

AC:

1836

AN:

3478

EpiCase

AF:

0.733

EpiControl

AF:

0.728

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Autosomal dominant nonsyndromic hearing loss 2A (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

3.8

(source)

DANN

Benign

0.55

PhyloP100

-4.4

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over