rs374877247

chr20-63419612-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_172107.4(KCNQ2):c.1301+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,608,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001489
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.83

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 20-63419612-G-A is Benign according to our data. Variant chr20-63419612-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138020.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000105 (16/152232) while in subpopulation AMR AF= 0.000327 (5/15286). AF 95% confidence interval is 0.000129. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.1301+7C>T		splice_region_variant, intron_variant		ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1301+7C>T		splice_region_variant, intron_variant		1	NM_172107.4	A1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000154 AC: 37 AN: 240060 Hom.: 0 AF XY: 0.000138 AC XY: 18 AN XY: 129978

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000450

Gnomad SAS exome AF: 0.0000343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000203 AC: 296 AN: 1456238 Hom.: 0 Cov.: 31 AF XY: 0.000199 AC XY: 144 AN XY: 723890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000386

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000506

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000889 Hom.: 0

Bravo AF: 0.000113

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2014

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. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	13
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
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: rs374877247; hg19: chr20-62050965;