1-40784108-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_004700.4(KCNQ4):c.15C>T(p.Pro5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 590,042 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (6 hom.)
• Consequence: KCNQ4 NM_004700.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.37

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-40784108-C-T is Benign according to our data. Variant chr1-40784108-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2918010.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000462 (205/443584) while in subpopulation NFE AF= 0.000496 (199/401476). AF 95% confidence interval is 0.000439. There are 6 homozygotes in gnomad4_exome. There are 101 alleles in male gnomad4_exome subpopulation. Median coverage is 5. This position pass quality control queck.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.15C>T	p.Pro5=	synonymous_variant	1/14	ENST00000347132.10
KCNQ4	NM_172163.3	c.15C>T	p.Pro5=	synonymous_variant	1/13
KCNQ4	XM_047434057.1	c.15C>T	p.Pro5=	synonymous_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.15C>T	p.Pro5=	synonymous_variant	1/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.15C>T	p.Pro5=	synonymous_variant	1/13	5		A1

Frequencies

GnomAD3 genomes AF: 0.0000410 AC: 6 AN: 146458 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000490

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: 0.0000607

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000462 AC: 205 AN: 443584 Hom.: 6 Cov.: 5 AF XY: 0.000474 AC XY: 101 AN XY: 213146

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.00

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: 0.000496

Gnomad4 OTH exome AF: 0.000339

GnomAD4 genome AF: 0.0000410 AC: 6 AN: 146458 Hom.: 0 Cov.: 32 AF XY: 0.0000281 AC XY: 2 AN XY: 71226

Gnomad4 AFR AF: 0.0000490

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: 0.0000607

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Benign	0.97

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: rs891485411; hg19: chr1-41249780;