1-40819423-A-T

Position:

• chr1-40819423-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_004700.4(KCNQ4):​c.785A>T​(p.Asp262Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.46

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 5 ACMG points.

• PM1: In a mutagenesis_site No effect on inhibition by potassium channel toxin SsTX. (size 0) in uniprot entity KCNQ4_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.785A>T	p.Asp262Val	missense_variant	5/14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.785A>T	p.Asp262Val	missense_variant	5/14	1	NM_004700.4	ENSP00000262916	P2
KCNQ4	ENST00000509682.6	c.785A>T	p.Asp262Val	missense_variant	5/13	5		ENSP00000423756	A1
KCNQ4	ENST00000443478.3	c.473A>T	p.Asp158Val	missense_variant	4/13	5		ENSP00000406735
KCNQ4	ENST00000506017.1	n.104A>T		non_coding_transcript_exon_variant	2/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461714 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727170

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 2A Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with autosomal dominant deafness 2A (MIM#600101). The exact mechanism exerted by premature termination codons remains unknown. Dominant negative is unlikely, as these mutant proteins lack the C-terminal necessary for heteromultimer formation (PMID: 34622280). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and moderate conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in a region where missense variants cluster within the C-terminal end of the ion transport domain (DECIPHER). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change, p.(Asp262Gly), has been previously classified as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in an individual with autosomal dominant nonsyndromic hearing loss but has been reported both without classification and as a VUS (PMIDs: 18941426, 32382995). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. CHO cells co-transfected with WT and p.(Asp262Val) had no measurable outward current compared to WT cells, indicating that the variant induced channel deficiency (PMID: 31995783). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Aug 20, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0020	.;D;D
Polyphen		1.0	D;D;P
Vest4		0.93, 0.81
MutPred		0.82		Loss of disorder (P = 0.0078);Loss of disorder (P = 0.0078);Loss of disorder (P = 0.0078);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358275; hg19: chr1-41285095;