chr1-40819913-G-A

Position:

chr1-40819913-G-A

Variant summary

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

The NM_004700.4(KCNQ4):c.873G>A(p.Pro291=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 1,611,670 control chromosomes in the GnomAD database, including 7,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 630 hom., cov: 33)

Exomes 𝑓: 0.094 ( 7227 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.84

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:

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=-0.7).

BP6

Variant 1-40819913-G-A is Benign according to our data. Variant chr1-40819913-G-A is described in ClinVar as [Benign]. Clinvar id is 45107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40819913-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4 linkuse as main transcript	c.873G>A	p.Pro291=	synonymous_variant	6/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10 linkuse as main transcript	c.873G>A	p.Pro291=	synonymous_variant	6/14	1	NM_004700.4	P2	P56696-1
KCNQ4	ENST00000509682.6 linkuse as main transcript	c.873G>A	p.Pro291=	synonymous_variant	6/13	5		A1	P56696-2
KCNQ4	ENST00000443478.3 linkuse as main transcript	c.561G>A	p.Pro187=	synonymous_variant	5/13	5
KCNQ4	ENST00000506017.1 linkuse as main transcript	n.192G>A		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes

AF:

0.0805

AC:

12244

AN:

152132

Hom.:

625

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0253

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.0794

Gnomad ASJ

AF:

0.0695

Gnomad EAS

AF:

0.211

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0930

Gnomad OTH

AF:

0.0903

GnomAD3 exomes

AF:

0.106

AC:

26742

AN:

251452

Hom.:

1692

AF XY:

0.107

AC XY:

14603

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.0798

Gnomad ASJ exome

AF:

0.0720

Gnomad EAS exome

AF:

0.225

Gnomad SAS exome

AF:

0.141

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.0965

Gnomad OTH exome

AF:

0.103

GnomAD4 exome

AF:

0.0942

AC:

137417

AN:

1459420

Hom.:

7227

Cov.:

AF XY:

0.0951

AC XY:

69033

AN XY:

726114

show subpopulations

Gnomad4 AFR exome

AF:

0.0230

Gnomad4 AMR exome

AF:

0.0791

Gnomad4 ASJ exome

AF:

0.0754

Gnomad4 EAS exome

AF:

0.190

Gnomad4 SAS exome

AF:

0.138

Gnomad4 FIN exome

AF:

0.128

Gnomad4 NFE exome

AF:

0.0890

Gnomad4 OTH exome

AF:

0.0928

GnomAD4 genome

AF:

0.0805

AC:

12253

AN:

152250

Hom.:

630

Cov.:

AF XY:

0.0834

AC XY:

6207

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0252

Gnomad4 AMR

AF:

0.0794

Gnomad4 ASJ

AF:

0.0695

Gnomad4 EAS

AF:

0.211

Gnomad4 SAS

AF:

0.138

Gnomad4 FIN

AF:

0.127

Gnomad4 NFE

AF:

0.0930

Gnomad4 OTH

AF:

0.0983

Alfa

AF:

0.0839

Hom.:

253

Bravo

AF:

0.0738

Asia WGS

AF:

0.164

AC:

568

AN:

3478

EpiCase

AF:

0.0925

EpiControl

AF:

0.0896

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Pro291Pro 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 8.7% (611/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs12117176). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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. -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.5

DANN

Benign

0.77

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

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