1-40835018-G-A

Variant names:

• chr1-40835018-G-A
• rs55964611
• NM_004700.4:c.1665G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004700.4(KCNQ4):​c.1665G>A​(p.Pro555Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,613,944 control chromosomes in the GnomAD database, including 1,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (122 hom., cov: 31)
  • Exomes 𝑓: 0.037 (1111 hom.)
• Consequence: KCNQ4 NM_004700.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -5.63
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.034).
• BP6: Variant 1-40835018-G-A is Benign according to our data. Variant chr1-40835018-G-A is described in ClinVar as Benign. ClinVar VariationId is 45103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0315 (4805/152320) while in subpopulation NFE AF = 0.0453 (3081/68026). AF 95% confidence interval is 0.044. There are 122 homozygotes in GnomAd4. There are 2309 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 122 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.1665G>A	p.Pro555Pro	synonymous	Exon 12 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.1503G>A	p.Pro501Pro	synonymous	Exon 11 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.1665G>A	p.Pro555Pro	synonymous	Exon 12 of 14	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.1605G>A	p.Pro535Pro	synonymous	Exon 12 of 14	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.1548G>A	p.Pro516Pro	synonymous	Exon 12 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4801 AN: 152202 Hom.: 121 Cov.: 31

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0624

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0301 AC: 7569 AN: 251452 AF XY: 0.0304

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0572

Gnomad NFE exome AF: 0.0441

Gnomad OTH exome AF: 0.0315

GnomAD4 exome AF: 0.0371 AC: 54282 AN: 1461624 Hom.: 1111 Cov.: 31 AF XY: 0.0364 AC XY: 26464 AN XY: 727118

African (AFR) AF: 0.0130 AC: 435 AN: 33476

American (AMR) AF: 0.0157 AC: 701 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 437 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39688

South Asian (SAS) AF: 0.00914 AC: 788 AN: 86252

European-Finnish (FIN) AF: 0.0578 AC: 3083 AN: 53376

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5764

European-Non Finnish (NFE) AF: 0.0421 AC: 46817 AN: 1111824

Other (OTH) AF: 0.0324 AC: 1957 AN: 60388

GnomAD4 genome AF: 0.0315 AC: 4805 AN: 152320 Hom.: 122 Cov.: 31 AF XY: 0.0310 AC XY: 2309 AN XY: 74480

African (AFR) AF: 0.0133 AC: 551 AN: 41576

American (AMR) AF: 0.0188 AC: 288 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00828 AC: 40 AN: 4832

European-Finnish (FIN) AF: 0.0624 AC: 662 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0453 AC: 3081 AN: 68026

Other (OTH) AF: 0.0284 AC: 60 AN: 2112

Alfa AF: 0.0312 Hom.: 34

Bravo AF: 0.0283

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0403

EpiControl AF: 0.0406

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	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	0.20
DANN	Benign	0.77
PhyloP100		-5.6
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: rs55964611; hg19: chr1-41300690; COSMIC: COSV61273121;