20-63400695-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_172107.4(KCNQ2):c.*5949G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000499 in 398,640 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: KCNQ2 NM_172107.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.06

Genes affected

KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041336715).
• BP6: Variant 20-63400695-C-T is Benign according to our data. Variant chr20-63400695-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2571140.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00044 (67/152350) while in subpopulation SAS AF= 0.00766 (37/4828). AF 95% confidence interval is 0.00572. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.*5949G>A		3_prime_UTR_variant	17/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.*5949G>A		3_prime_UTR_variant	17/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000536 AC: 132 AN: 246290 Hom.: 1 Cov.: 0 AF XY: 0.000633 AC XY: 79 AN XY: 124818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000942

Gnomad4 ASJ exome AF: 0.00455

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74506

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000302

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

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

KCNQ2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.52
Dann	Benign	0.83
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0041	T
Sift4G	Uncertain	0.054	T
Vest4		0.042
MVP		0.21
GERP RS		-3.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs577094863; hg19: chr20-62032048;