rs537008263

Positions:

• chr1-40838530-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004700.4(KCNQ4):​c.*7T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.644

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000328 (50/152310) while in subpopulation AFR AF= 0.0012 (50/41574). AF 95% confidence interval is 0.000937. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.*7T>C		3_prime_UTR_variant	14/14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3	c.*7T>C		3_prime_UTR_variant	13/13		NP_751895.1
KCNQ4	XM_017002792.2	c.*7T>C		3_prime_UTR_variant	11/11		XP_016858281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.*7T>C		3_prime_UTR_variant	14/14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000443478.3	c.*7T>C		3_prime_UTR_variant	13/13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.1414T>C		non_coding_transcript_exon_variant	11/11	2
KCNQ4	ENST00000509682.6	c.*7T>C		downstream_gene_variant		5		ENSP00000423756.2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 251100 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135822

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461240 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 726996

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74482

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000280

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 15, 2015

The c.*7T>C variant in KCNQ4 has not been previously reported in individuals wit h hearing loss, but has been identified in 9/10338 African chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs537008 263). Although this variant has been seen in the general population, its freque ncy is not high enough to rule out a pathogenic role. This variant occurs in the 3' untranslated region (3' UTR) and does not affect the coding sequence of the gene. Although this region can contain elements that regulate mRNA, there is no obvious predicted effect of this variant. In summary, the clinical significance of the c.*7T>C variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs537008263; hg19: chr1-41304202;