rs142453905

Positions:

chr1-40831116-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004700.4(KCNQ4):c.1325T>C(p.Met442Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,607,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.07

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 links:

KCNQ4 (HGNC:):

KCNQ4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011752695).

BP6

Variant 1-40831116-T-C is Benign according to our data. Variant chr1-40831116-T-C is described in ClinVar as [Benign]. Clinvar id is 163754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4 linkuse as main transcript	c.1325T>C	p.Met442Thr	missense_variant	10/14	ENST00000347132.10	NP_004691.2	P56696-1B3KQH8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ4	ENST00000347132.10 linkuse as main transcript	c.1325T>C	p.Met442Thr	missense_variant	10/14	1	NM_004700.4	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000509682.6 linkuse as main transcript	c.1163T>C	p.Met388Thr	missense_variant	9/13	5		ENSP00000423756.2	P56696-2
KCNQ4	ENST00000443478.3 linkuse as main transcript	c.905T>C	p.Met302Thr	missense_variant	9/13	5		ENSP00000406735.3	H0Y6N7
KCNQ4	ENST00000506017.1 linkuse as main transcript	n.644T>C		non_coding_transcript_exon_variant	7/11	2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.000327

AC:

AN:

235548

Hom.:

AF XY:

0.000328

AC XY:

AN XY:

127998

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000297

Gnomad ASJ exome

AF:

0.00565

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000958

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.000189

AC:

275

AN:

1455560

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

138

AN XY:

723486

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000272

Gnomad4 ASJ exome

AF:

0.00636

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000640

Gnomad4 OTH exome

AF:

0.000432

GnomAD4 genome

AF:

0.000164

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000323

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 08, 2019

The p.Met442Thr variant in KCNQ4 is classified as benign because it has been identified in 0.5% (56/10022) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein. ACMG/AMP Criteria applied: BA1, BP4. -

Autosomal dominant nonsyndromic hearing loss 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.37

T;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

.;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.5

.;D;D

REVEL

Uncertain

0.37

Sift

Benign

0.39

.;T;T

Sift4G

Benign

0.49

.;T;T

Polyphen

0.0050

B;B;B

Vest4

0.51, 0.49

MVP

0.52

MPC

0.15

ClinPred

0.043

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over