rs876657480

Variant names:

• chr1-40822298-T-TC
• rs876657480
• NM_004700.4:c.1042-11dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004700.4(KCNQ4):​c.1042-11dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,611,094 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: KCNQ4 NM_004700.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.824
• Publications: 0 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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-40822298-T-TC is Benign according to our data. Variant chr1-40822298-T-TC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000204 (31/152006) while in subpopulation SAS AF = 0.00228 (11/4814). AF 95% confidence interval is 0.00128. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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.1042-11dupC		intron	N/A	NP_004691.2
	KCNQ4	NM_172163.3		c.1042-11dupC		intron	N/A	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.1042-16_1042-15insC		intron	N/A	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.1042-16_1042-15insC		intron	N/A	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.1042-16_1042-15insC		intron	N/A	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 151888 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000503 AC: 126 AN: 250674 AF XY: 0.000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000512

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000323 AC: 472 AN: 1459088 Hom.: 3 Cov.: 32 AF XY: 0.000387 AC XY: 281 AN XY: 726144

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.000134 AC: 6 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00285 AC: 246 AN: 86206

European-Finnish (FIN) AF: 0.000507 AC: 27 AN: 53220

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5758

European-Non Finnish (NFE) AF: 0.000146 AC: 162 AN: 1109636

Other (OTH) AF: 0.000298 AC: 18 AN: 60318

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4814

European-Finnish (FIN) AF: 0.000473 AC: 5 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism

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: rs876657480; hg19: chr1-41287970;