chr1-40827977-C-T

Variant names:

• chr1-40827977-C-T
• rs4660176
• NM_004700.4:c.1293-3107C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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]

KCNQ4 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1293-3107C>T		intron_variant	Intron 9 of 13	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1293-3107C>T		intron_variant	Intron 9 of 13	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.1131-3107C>T		intron_variant	Intron 8 of 12	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.872+1283C>T		intron_variant	Intron 8 of 12	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.612-3107C>T		intron_variant	Intron 6 of 10	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

African (AFR) AF: 0.212 AC: 8784 AN: 41502

American (AMR) AF: 0.299 AC: 4579 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3468

East Asian (EAS) AF: 0.275 AC: 1423 AN: 5176

South Asian (SAS) AF: 0.259 AC: 1251 AN: 4826

European-Finnish (FIN) AF: 0.386 AC: 4078 AN: 10560

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27932 AN: 67972

Other (OTH) AF: 0.345 AC: 727 AN: 2110

Alfa AF: 0.389 Hom.: 16418

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
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4660176; hg19: chr1-41293649;