rs61737409

chr20-63413494-G-Achr20-63413494-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_172107.4(KCNQ2):c.1719C>T(p.Ala573=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,456 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (34 hom.)
• Consequence: KCNQ2 NM_172107.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.78

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 20-63413494-G-A is Benign according to our data. Variant chr20-63413494-G-A is described in ClinVar as [Benign]. Clinvar id is 129338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00383 (584/152338) while in subpopulation EAS AF= 0.034 (176/5180). AF 95% confidence interval is 0.0299. There are 5 homozygotes in gnomad4. There are 320 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 586 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.1719C>T	p.Ala573=	synonymous_variant	15/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1719C>T	p.Ala573=	synonymous_variant	15/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152220 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00665 AC: 1670 AN: 251054 Hom.: 28 AF XY: 0.00686 AC XY: 932 AN XY: 135842

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0434

Gnomad SAS exome AF: 0.00869

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00405

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00420 AC: 6130 AN: 1461118 Hom.: 34 Cov.: 32 AF XY: 0.00425 AC XY: 3090 AN XY: 726866

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0338

Gnomad4 SAS exome AF: 0.00721

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00325

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.00383 AC: 584 AN: 152338 Hom.: 5 Cov.: 33 AF XY: 0.00430 AC XY: 320 AN XY: 74486

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.0340

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00353

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00439 Hom.: 6

Bravo AF: 0.00441

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00350

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.36
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61737409; hg19: chr20-62044847; COSMIC: COSV60546161; COSMIC: COSV60546161;