rs12117176

chr1-40819913-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.84

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]

ACMG classification

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	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	c.873G>A	p.Pro291=	synonymous_variant	6/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.873G>A	p.Pro291=	synonymous_variant	6/13	5		A1
KCNQ4	ENST00000443478.3	c.561G>A	p.Pro187=	synonymous_variant	5/13	5
KCNQ4	ENST00000506017.1	n.192G>A		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes AF: 0.0805 AC: 12244 AN: 152132 Hom.: 625 Cov.: 33

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

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.: 33 AF XY: 0.0951 AC XY: 69033 AN XY: 726114

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.: 33 AF XY: 0.0834 AC XY: 6207 AN XY: 74428

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

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

Other links and lift over

dbSNP: rs12117176; hg19: chr1-41285585; COSMIC: COSV61272028;