1-40784146-C-T

Position:

• chr1-40784146-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_004700.4(KCNQ4):​c.53C>T​(p.Ala18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000565 in 885,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.745

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13017476).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.53C>T	p.Ala18Val	missense_variant	1/14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3	c.53C>T	p.Ala18Val	missense_variant	1/13		NP_751895.1
KCNQ4	XM_047434057.1	c.53C>T	p.Ala18Val	missense_variant	1/13		XP_047290013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.53C>T	p.Ala18Val	missense_variant	1/14	1	NM_004700.4	ENSP00000262916	P2
KCNQ4	ENST00000509682.6	c.53C>T	p.Ala18Val	missense_variant	1/13	5		ENSP00000423756	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000565 AC: 5 AN: 885420 Hom.: 0 Cov.: 14 AF XY: 0.00000940 AC XY: 4 AN XY: 425636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000385

Gnomad4 OTH exome AF: 0.0000328

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 12, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ4 protein function. This variant has not been reported in the literature in individuals affected with KCNQ4-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 18 of the KCNQ4 protein (p.Ala18Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.56	.;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	-0.34	N;N;N
MutationTaster	Benign	0.85	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.37	.;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.55	.;T;T
Sift4G	Benign	0.44	.;T;T
Polyphen		0.047	B;B;B
Vest4		0.093, 0.10
MutPred		0.094		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.61
MPC		1.1
ClinPred		0.23	T
GERP RS		1.7
Varity_R		0.047
gMVP		0.39

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: rs1347676173; hg19: chr1-41249818;