rs137896524

Positions:

• chr1-40820191-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004700.4(KCNQ4):​c.972G>A​(p.Leu324=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,610,128 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (40 hom.)
• Consequence: KCNQ4 NM_004700.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.07

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 -16 ACMG points.

• BP6: Variant 1-40820191-G-A is Benign according to our data. Variant chr1-40820191-G-A is described in ClinVar as [Benign]. Clinvar id is 163750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40820191-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00142 (216/152336) while in subpopulation SAS AF= 0.0188 (91/4828). AF 95% confidence interval is 0.0157. There are 1 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.972G>A	p.Leu324=	synonymous_variant	7/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.972G>A	p.Leu324=	synonymous_variant	7/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.972G>A	p.Leu324=	synonymous_variant	7/13	5		A1
KCNQ4	ENST00000443478.3	c.660G>A	p.Leu220=	synonymous_variant	6/13	5
KCNQ4	ENST00000506017.1	n.291G>A		non_coding_transcript_exon_variant	4/11	2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00320 AC: 774 AN: 242222 Hom.: 9 AF XY: 0.00420 AC XY: 551 AN XY: 131202

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.000325

Gnomad ASJ exome AF: 0.00955

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0188

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000852

Gnomad OTH exome AF: 0.00288

GnomAD4 exome AF: 0.00209 AC: 3045 AN: 1457792 Hom.: 40 Cov.: 32 AF XY: 0.00273 AC XY: 1981 AN XY: 724900

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000294

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0199

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000734

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00152 AC XY: 113 AN XY: 74496

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00163 Hom.: 1

Bravo AF: 0.00102

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2015	p.Leu324Leu in exon 7 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 2.4% (297/12304) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs137896524). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal dominant nonsyndromic hearing loss 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2018	- -
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	-0.38
CADD	Benign	16
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137896524; hg19: chr1-41285863; COSMIC: COSV100714311;