rs55925184

Positions:

• chr1-40835010-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004700.4(KCNQ4):​c.1657C>T​(p.Leu553=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,614,046 control chromosomes in the GnomAD database, including 2,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (102 hom., cov: 31)
  • Exomes 𝑓: 0.049 (2030 hom.)
• Consequence: KCNQ4 NM_004700.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.06

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 1-40835010-C-T is Benign according to our data. Variant chr1-40835010-C-T is described in ClinVar as [Benign]. Clinvar id is 45102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40835010-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1657C>T	p.Leu553=	synonymous_variant	12/14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1657C>T	p.Leu553=	synonymous_variant	12/14	1	NM_004700.4	ENSP00000262916	P2
KCNQ4	ENST00000509682.6	c.1495C>T	p.Leu499=	synonymous_variant	11/13	5		ENSP00000423756	A1
KCNQ4	ENST00000443478.3	c.1240C>T	p.Leu414=	synonymous_variant	11/13	5		ENSP00000406735
KCNQ4	ENST00000506017.1	n.976C>T		non_coding_transcript_exon_variant	9/11	2

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5004 AN: 152234 Hom.: 102 Cov.: 31

Gnomad AFR AF: 0.00955

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0520

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0351 AC: 8823 AN: 251452 Hom.: 227 AF XY: 0.0376 AC XY: 5116 AN XY: 135914

Gnomad AFR exome AF: 0.00867

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0531

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0480

Gnomad OTH exome AF: 0.0399

GnomAD4 exome AF: 0.0495 AC: 72314 AN: 1461694 Hom.: 2030 Cov.: 31 AF XY: 0.0501 AC XY: 36411 AN XY: 727148

Gnomad4 AFR exome AF: 0.00720

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0201

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0532

Gnomad4 FIN exome AF: 0.0220

Gnomad4 NFE exome AF: 0.0557

Gnomad4 OTH exome AF: 0.0428

GnomAD4 genome AF: 0.0328 AC: 5000 AN: 152352 Hom.: 102 Cov.: 31 AF XY: 0.0306 AC XY: 2283 AN XY: 74494

Gnomad4 AFR AF: 0.00950

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0204

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0520

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0443 Hom.: 115

Bravo AF: 0.0321

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0532

EpiControl AF: 0.0490

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Leu553Leu in Exon 12 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 5.0% (350/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs55925184). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 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:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Autosomal dominant nonsyndromic hearing loss 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	6.7
DANN	Benign	0.72

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

Other links and lift over

dbSNP: rs55925184; hg19: chr1-41300682;