1-40819881-T-C

Position:

chr1-40819881-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004700.4(KCNQ4):c.841T>C(p.Leu281Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,613,114 control chromosomes in the GnomAD database, including 1,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 156 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1635 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.26

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 1-40819881-T-C is Benign according to our data. Variant chr1-40819881-T-C is described in ClinVar as [Benign]. Clinvar id is 45106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40819881-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4 linkuse as main transcript	c.841T>C	p.Leu281Leu	synonymous_variant	6/14	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.841T>C	p.Leu281Leu	synonymous_variant	6/14	1	NM_004700.4	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000509682.6 linkuse as main transcript	c.841T>C	p.Leu281Leu	synonymous_variant	6/13	5		ENSP00000423756.2	P56696-2
KCNQ4	ENST00000443478.3 linkuse as main transcript	c.526T>C	p.Leu176Leu	synonymous_variant	5/13	5		ENSP00000406735.3	H0Y6N7
KCNQ4	ENST00000506017.1 linkuse as main transcript	n.160T>C		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes

AF:

0.0379

AC:

5766

AN:

152166

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.0538

Gnomad ASJ

AF:

0.0732

Gnomad EAS

AF:

0.0524

Gnomad SAS

AF:

0.0335

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0645

GnomAD3 exomes

AF:

0.0400

AC:

10066

AN:

251490

Hom.:

229

AF XY:

0.0418

AC XY:

5678

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.0338

Gnomad ASJ exome

AF:

0.0670

Gnomad EAS exome

AF:

0.0555

Gnomad SAS exome

AF:

0.0321

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.0472

Gnomad OTH exome

AF:

0.0484

GnomAD4 exome

AF:

0.0452

AC:

66036

AN:

1460830

Hom.:

1635

Cov.:

AF XY:

0.0451

AC XY:

32772

AN XY:

726814

show subpopulations

Gnomad4 AFR exome

AF:

0.0142

Gnomad4 AMR exome

AF:

0.0352

Gnomad4 ASJ exome

AF:

0.0670

Gnomad4 EAS exome

AF:

0.0490

Gnomad4 SAS exome

AF:

0.0337

Gnomad4 FIN exome

AF:

0.0169

Gnomad4 NFE exome

AF:

0.0478

Gnomad4 OTH exome

AF:

0.0481

GnomAD4 genome

AF:

0.0378

AC:

5755

AN:

152284

Hom.:

156

Cov.:

AF XY:

0.0366

AC XY:

2725

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0146

Gnomad4 AMR

AF:

0.0537

Gnomad4 ASJ

AF:

0.0732

Gnomad4 EAS

AF:

0.0516

Gnomad4 SAS

AF:

0.0340

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.0478

Gnomad4 OTH

AF:

0.0629

Alfa

AF:

0.0418

Hom.:

Bravo

AF:

0.0403

Asia WGS

AF:

0.0430

AC:

149

AN:

3478

EpiCase

AF:

0.0576

EpiControl

AF:

0.0549

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Leu281Leu 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 4.7% (333/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs55737429). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Autosomal dominant nonsyndromic hearing loss 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.5

DANN

Benign

0.50

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