chr1-40784274-C-T

Position:

• chr1-40784274-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004700.4(KCNQ4):​c.181C>T​(p.Pro61Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,377,190 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P61L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28138143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.181C>T	p.Pro61Ser	missense_variant	1/14	ENST00000347132.10
KCNQ4	NM_172163.3	c.181C>T	p.Pro61Ser	missense_variant	1/13
KCNQ4	XM_047434057.1	c.181C>T	p.Pro61Ser	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.181C>T	p.Pro61Ser	missense_variant	1/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.181C>T	p.Pro61Ser	missense_variant	1/13	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1377190 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 681724

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: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.30e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.181C>T (p.P61S) alteration is located in exon 1 (coding exon 1) of the KCNQ4 gene. This alteration results from a C to T substitution at nucleotide position 181, causing the proline (P) at amino acid position 61 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.56	.;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.65	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.31	.;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.15	.;T;T
Sift4G	Benign	0.15	.;T;T
Polyphen		0.21	B;B;B
Vest4		0.18, 0.24
MutPred		0.19		Gain of phosphorylation at P61 (P = 0.007);Gain of phosphorylation at P61 (P = 0.007);Gain of phosphorylation at P61 (P = 0.007);
MVP		0.50
MPC		1.1
ClinPred		0.23	T
GERP RS		2.3
Varity_R		0.072
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-41249946;