rs200426006

chr1-40824270-G-Achr1-40824270-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004700.4(KCNQ4):c.1292+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,603,776 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (3 hom.)
• Consequence: KCNQ4 NM_004700.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.543

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-40824270-G-A is Benign according to our data. Variant chr1-40824270-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00192 (292/152296) while in subpopulation AFR AF= 0.00626 (260/41566). AF 95% confidence interval is 0.00563. There are 0 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 291 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.1292+12G>A		intron_variant		ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1292+12G>A		intron_variant		1	NM_004700.4	P2
KCNQ4	ENST00000443478.3	c.816+1868G>A		intron_variant		5
KCNQ4	ENST00000509682.6	c.1130+1868G>A		intron_variant		5		A1
KCNQ4	ENST00000506017.1	n.611+12G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00623

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000697 AC: 152 AN: 218194 Hom.: 1 AF XY: 0.000703 AC XY: 85 AN XY: 120956

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.000331

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000238

Gnomad SAS exome AF: 0.00171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000318

Gnomad OTH exome AF: 0.000369

GnomAD4 exome AF: 0.000315 AC: 457 AN: 1451480 Hom.: 3 Cov.: 33 AF XY: 0.000369 AC XY: 266 AN XY: 721570

Gnomad4 AFR exome AF: 0.00640

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000734

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.00191 AC XY: 142 AN XY: 74468

Gnomad4 AFR AF: 0.00626

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.00184

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

1292+12G>A in Intron 09 of KCNQ4: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 0.5% (17/3628) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS). -

Autosomal dominant nonsyndromic hearing loss 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	6.5
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs200426006; hg19: chr1-41289942;