chr1-40817249-C-T

Variant names:

• chr1-40817249-C-T
• rs13374845
• NM_004700.4:c.315-16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004700.4(KCNQ4):​c.315-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,608,150 control chromosomes in the GnomAD database, including 17,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1925 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15728 hom.)
• Consequence: KCNQ4 NM_004700.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.288
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-40817249-C-T is Benign according to our data. Variant chr1-40817249-C-T is described in ClinVar as Benign. ClinVar VariationId is 259519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004700.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	NM_004700.4	MANE Select	c.315-16C>T		intron	N/A	NP_004691.2
	KCNQ4	NM_172163.3		c.315-16C>T		intron	N/A	NP_751895.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.315-16C>T		intron	N/A	ENSP00000262916.6
	KCNQ4	ENST00000509682.6	TSL:5	c.315-16C>T		intron	N/A	ENSP00000423756.2
	KCNQ4	ENST00000443478.3	TSL:5	c.-17C>T		upstream_gene	N/A	ENSP00000406735.3

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23666 AN: 152146 Hom.: 1919 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.157 AC: 38664 AN: 246148 AF XY: 0.157

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.310

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.144 AC: 209651 AN: 1455886 Hom.: 15728 Cov.: 30 AF XY: 0.144 AC XY: 104377 AN XY: 724158

African (AFR) AF: 0.169 AC: 5652 AN: 33378

American (AMR) AF: 0.120 AC: 5351 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3688 AN: 26042

East Asian (EAS) AF: 0.275 AC: 10914 AN: 39634

South Asian (SAS) AF: 0.172 AC: 14756 AN: 85632

European-Finnish (FIN) AF: 0.144 AC: 7686 AN: 53240

Middle Eastern (MID) AF: 0.171 AC: 984 AN: 5760

European-Non Finnish (NFE) AF: 0.137 AC: 151409 AN: 1107552

Other (OTH) AF: 0.153 AC: 9211 AN: 60128

GnomAD4 genome AF: 0.156 AC: 23685 AN: 152264 Hom.: 1925 Cov.: 32 AF XY: 0.157 AC XY: 11704 AN XY: 74440

African (AFR) AF: 0.169 AC: 7027 AN: 41548

American (AMR) AF: 0.143 AC: 2188 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3472

East Asian (EAS) AF: 0.294 AC: 1521 AN: 5166

South Asian (SAS) AF: 0.170 AC: 822 AN: 4824

European-Finnish (FIN) AF: 0.141 AC: 1493 AN: 10608

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9521 AN: 68024

Other (OTH) AF: 0.187 AC: 396 AN: 2116

Alfa AF: 0.143 Hom.: 302

Bravo AF: 0.157

Asia WGS AF: 0.236 AC: 819 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant nonsyndromic hearing loss 2A Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.0
DANN	Benign	0.28
PhyloP100		0.29
PromoterAI		-0.00050	Neutral
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: rs13374845; hg19: chr1-41282921; COSMIC: COSV61272565; COSMIC: COSV61272565;