1-40784268-C-T

Variant names:

• chr1-40784268-C-T
• rs772056095
• NM_004700.4:c.175C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004700.4(KCNQ4):​c.175C>T​(p.Pro59Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,358,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. P59L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (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: -0.0500

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1570042).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.175C>T	p.Pro59Ser	missense_variant	Exon 1 of 14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3	c.175C>T	p.Pro59Ser	missense_variant	Exon 1 of 13		NP_751895.1
KCNQ4	XM_047434057.1	c.175C>T	p.Pro59Ser	missense_variant	Exon 1 of 13		XP_047290013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.175C>T	p.Pro59Ser	missense_variant	Exon 1 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.175C>T	p.Pro59Ser	missense_variant	Exon 1 of 13	5		ENSP00000423756.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000511 AC: 6 AN: 117328 Hom.: 0 AF XY: 0.0000454 AC XY: 3 AN XY: 66086

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000299

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 14 AN: 1358762 Hom.: 0 Cov.: 31 AF XY: 0.0000149 AC XY: 10 AN XY: 671516

Gnomad4 AFR exome AF: 0.0000357

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.38e-7

Gnomad4 OTH exome AF: 0.0000357

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000389 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.175C>T (p.P59S) 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 175, causing the proline (P) at amino acid position 59 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	0.077
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.54	.;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	0.76	N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.16	.;N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.46	.;T;T
Polyphen		0.34	B;B;P
Vest4		0.090, 0.11
MutPred		0.21		Gain of phosphorylation at P59 (P = 0.0078);Gain of phosphorylation at P59 (P = 0.0078);Gain of phosphorylation at P59 (P = 0.0078);
MVP		0.76
MPC		2.3
ClinPred		0.12	T
GERP RS		1.7
Varity_R		0.059
gMVP		0.55

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: rs772056095; hg19: chr1-41249940;