rs4660176

Positions:

• chr1-40827977-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004700.4(KCNQ4):​c.1293-3107C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 152,114 control chromosomes in the GnomAD database, including 9,109 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (9109 hom., cov: 33)
• Consequence: KCNQ4 NM_004700.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.151

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1293-3107C>T		intron_variant		ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1293-3107C>T		intron_variant		1	NM_004700.4	ENSP00000262916	P2
KCNQ4	ENST00000443478.3	c.873+1283C>T		intron_variant		5		ENSP00000406735
KCNQ4	ENST00000509682.6	c.1131-3107C>T		intron_variant		5		ENSP00000423756	A1
KCNQ4	ENST00000506017.1	n.612-3107C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50762 AN: 151996 Hom.: 9106 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.344

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.334 AC: 50779 AN: 152114 Hom.: 9109 Cov.: 33 AF XY: 0.329 AC XY: 24468 AN XY: 74360

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.299

Gnomad4 ASJ AF: 0.417

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.386

Gnomad4 NFE AF: 0.411

Gnomad4 OTH AF: 0.345

Alfa AF: 0.397 Hom.: 13603

Bravo AF: 0.324

Asia WGS AF: 0.269 AC: 937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.88

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: rs4660176; hg19: chr1-41293649;