rs375363057

chr20-63439718-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3 PP5_Moderate

The NM_172107.4(KCNQ2):c.817-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,447,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9963
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.284

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 Uncertain_significance. Variant got 3 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 20-63439718-C-T is Pathogenic according to our data. Variant chr20-63439718-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 579506.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.817-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.817-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000622 AC: 9 AN: 1447562 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 721184

Gnomad4 AFR exome AF: 0.0000301

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: 0.00000728

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 579506). This variant has been observed in individual(s) with clinical features of KCNQ2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the KCNQ2 gene. It does not directly change the encoded amino acid sequence of the KCNQ2 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
Cadd	Pathogenic	26
Dann	Benign	0.55
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.086	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N
Sift4G	Pathogenic	0.0	D
MVP		0.26
GERP RS		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.87		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs375363057; hg19: chr20-62071071; COSMIC: COSV100610746; COSMIC: COSV100610746;