rs12143503

Variant names:

• chr1-40819919-A-G
• rs12143503
• NM_004700.4:c.879A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004700.4(KCNQ4):​c.879A>G​(p.Thr293Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.093 in 1,612,286 control chromosomes in the GnomAD database, including 7,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene KCNQ4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.080 (630 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7245 hom.)
• Consequence: KCNQ4 NM_004700.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.56
• Publications: 16 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
• 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

Specifications for KCNQ4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.019).
• BP6: Variant 1-40819919-A-G is Benign according to our data. Variant chr1-40819919-A-G is described in ClinVar as Benign. ClinVar VariationId is 45108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	NM_004700.4	MANE Select	c.879A>G	p.Thr293Thr	synonymous	Exon 6 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.879A>G	p.Thr293Thr	synonymous	Exon 6 of 13	NP_751895.1	P56696-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.879A>G	p.Thr293Thr	synonymous	Exon 6 of 14	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.879A>G	p.Thr293Thr	synonymous	Exon 6 of 14	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.879A>G	p.Thr293Thr	synonymous	Exon 6 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12226 AN: 152114 Hom.: 625 Cov.: 32

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.0694

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0930

Gnomad OTH AF: 0.0903

GnomAD2 exomes AF: 0.106 AC: 26767 AN: 251438 AF XY: 0.108

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.0796

Gnomad ASJ exome AF: 0.0720

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0965

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0944 AC: 137787 AN: 1460054 Hom.: 7245 Cov.: 33 AF XY: 0.0953 AC XY: 69199 AN XY: 726390

African (AFR) AF: 0.0223 AC: 746 AN: 33462

American (AMR) AF: 0.0789 AC: 3529 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 1971 AN: 26130

East Asian (EAS) AF: 0.192 AC: 7605 AN: 39688

South Asian (SAS) AF: 0.139 AC: 11947 AN: 86176

European-Finnish (FIN) AF: 0.128 AC: 6848 AN: 53406

Middle Eastern (MID) AF: 0.0812 AC: 468 AN: 5764

European-Non Finnish (NFE) AF: 0.0892 AC: 99066 AN: 1110360

Other (OTH) AF: 0.0929 AC: 5607 AN: 60352

GnomAD4 genome AF: 0.0804 AC: 12233 AN: 152232 Hom.: 630 Cov.: 32 AF XY: 0.0833 AC XY: 6198 AN XY: 74434

African (AFR) AF: 0.0246 AC: 1022 AN: 41556

American (AMR) AF: 0.0795 AC: 1216 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0694 AC: 241 AN: 3472

East Asian (EAS) AF: 0.212 AC: 1095 AN: 5162

South Asian (SAS) AF: 0.138 AC: 667 AN: 4826

European-Finnish (FIN) AF: 0.127 AC: 1352 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0929 AC: 6319 AN: 67990

Other (OTH) AF: 0.0984 AC: 208 AN: 2114

Alfa AF: 0.0848 Hom.: 304

Bravo AF: 0.0738

Asia WGS AF: 0.164 AC: 568 AN: 3478

EpiCase AF: 0.0924

EpiControl AF: 0.0898

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.0
DANN	Benign	0.50
PhyloP100		-2.6
Mutation Taster		=99/1	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: rs12143503; hg19: chr1-41285591; COSMIC: COSV61272035;