1-40784173-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004700.4(KCNQ4):c.80C>G(p.Thr27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,116,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T27T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0820

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2784923).
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.80C>G	p.Thr27Arg	missense_variant	1/14	ENST00000347132.10
KCNQ4	NM_172163.3	c.80C>G	p.Thr27Arg	missense_variant	1/13
KCNQ4	XM_047434057.1	c.80C>G	p.Thr27Arg	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.80C>G	p.Thr27Arg	missense_variant	1/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.80C>G	p.Thr27Arg	missense_variant	1/13	5		A1

Frequencies

GnomAD3 genomes AF: 0.000102 AC: 15 AN: 147112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 10 AN: 969284 Hom.: 0 Cov.: 19 AF XY: 0.00000854 AC XY: 4 AN XY: 468144

Gnomad4 AFR exome AF: 0.000383

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: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000109 AC: 16 AN: 147222 Hom.: 0 Cov.: 32 AF XY: 0.000112 AC XY: 8 AN XY: 71724

Gnomad4 AFR AF: 0.000367

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000151

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000982

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

Invitae

Feb 21, 2023

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 27 of the KCNQ4 protein (p.Thr27Arg). This variant is present in population databases (no rsID available, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with KCNQ4-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.56	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
Polyphen		0.98	D;D;D
Vest4		0.15, 0.20
MutPred		0.22		Loss of glycosylation at T27 (P = 0.0323);Loss of glycosylation at T27 (P = 0.0323);Loss of glycosylation at T27 (P = 0.0323);
MVP		0.77
MPC		1.6
ClinPred		0.41	T
GERP RS		0.46
Varity_R		0.13
gMVP		0.63

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: rs1001249688; hg19: chr1-41249845;