chr1-40784248-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_004700.4(KCNQ4):c.155T>A(p.Leu52Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000947 in 1,372,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.74

Publications

0 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: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3550654).

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.155T>A	p.Leu52Gln	missense	Exon 1 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.155T>A	p.Leu52Gln	missense	Exon 1 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.155T>A	p.Leu52Gln	missense	Exon 1 of 14	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000967337.1		c.155T>A	p.Leu52Gln	missense	Exon 1 of 14	ENSP00000637396.1
KCNQ4	ENST00000967338.1		c.155T>A	p.Leu52Gln	missense	Exon 1 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

21596

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000899

AC:

AN:

1223104

Hom.:

Cov.:

AF XY:

0.0000150

AC XY:

AN XY:

599628

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23378

American (AMR)

AF:

0.00

AC:

AN:

11664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16414

East Asian (EAS)

AF:

0.00

AC:

AN:

26440

South Asian (SAS)

AF:

0.000125

AC:

AN:

55830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3774

European-Non Finnish (NFE)

AF:

0.00000299

AC:

AN:

1004230

Other (OTH)

AF:

0.0000202

AC:

AN:

49510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000134

AC:

AN:

149702

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41060

American (AMR)

AF:

0.00

AC:

AN:

15104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5012

South Asian (SAS)

AF:

0.000416

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67070

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant nonsyndromic hearing loss 2A (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Benign

0.87

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.36

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.9

PhyloP100

1.7

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.44

Sift

Benign

0.053

Sift4G

Benign

0.21

Polyphen

0.84

Vest4

0.23

MutPred

0.19

Loss of catalytic residue at L52 (P = 0.1365)

MVP

0.74

MPC

1.6

ClinPred

0.37

GERP RS

1.9

PromoterAI

0.033

Neutral

(source)

Varity_R

0.33

gMVP

0.54

Mutation Taster

=70/30

polymorphism

(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

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