chr1-40784233-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting

The NM_004700.4(KCNQ4):c.140T>C(p.Leu47Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,297,126 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 Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.11

Publications

9 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_pathogenic. The variant received 6 ACMG points.

PP5

Variant 1-40784233-T-C is Pathogenic according to our data. Variant chr1-40784233-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 585006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.37299556). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000027 (31/1148478) while in subpopulation EAS AF = 0.00132 (31/23568). AF 95% confidence interval is 0.000952. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.140T>C	p.Leu47Pro	missense	Exon 1 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.140T>C	p.Leu47Pro	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.140T>C	p.Leu47Pro	missense	Exon 1 of 14	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000967337.1		c.140T>C	p.Leu47Pro	missense	Exon 1 of 14	ENSP00000637396.1
KCNQ4	ENST00000967338.1		c.140T>C	p.Leu47Pro	missense	Exon 1 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148648

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:

0.000401

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1148478

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

559294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22022

American (AMR)

AF:

0.00

AC:

AN:

8178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14026

East Asian (EAS)

AF:

0.00132

AC:

AN:

23568

South Asian (SAS)

AF:

0.00

AC:

AN:

43898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3246

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

961862

Other (OTH)

AF:

0.00

AC:

AN:

45314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

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:

0.0000135

AC:

AN:

148648

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40732

American (AMR)

AF:

0.00

AC:

AN:

14994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.000401

AC:

AN:

4988

South Asian (SAS)

AF:

0.00

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66772

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

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:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant nonsyndromic hearing loss 2A (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Benign

0.90

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.37

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.3

PhyloP100

2.1

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.36

Sift

Benign

0.095

Sift4G

Uncertain

0.0030

Polyphen

0.017

Vest4

0.35

MutPred

0.24

Loss of stability (P = 0.0178)

MVP

0.75

MPC

2.2

ClinPred

0.22

GERP RS

1.9

PromoterAI

-0.14

Neutral

(source)

Varity_R

0.49

gMVP

0.71

Mutation Taster

=21/79

disease causing (ClinVar)

(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