rs35430888

Variant names:

• chr20-63428399-C-A
• rs35430888
• NM_172107.4:c.1185G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63428399-C-A
• chr20-63428399-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_172107.4(KCNQ2):​c.1185G>T​(p.Arg395Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.994

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.1185G>T	p.Arg395Ser	missense_variant	Exon 10 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1185G>T	p.Arg395Ser	missense_variant	Exon 10 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433750 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 709918

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;.;T;T;T;T;T;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	2.0	M;.;.;.;.;.;M;.;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	.;.;.;.;N;.;N;.;N;.
REVEL	Pathogenic	0.73
Sift	Benign	0.32	.;.;.;.;T;.;T;.;T;.
Sift4G	Benign	0.53	T;T;T;T;T;.;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D
Vest4		0.70
MutPred		0.39		Gain of ubiquitination at K400 (P = 0.0251);.;.;.;.;.;Gain of ubiquitination at K400 (P = 0.0251);.;.;Gain of ubiquitination at K400 (P = 0.0251);
MVP		0.98
MPC		1.3
ClinPred		0.76	D
GERP RS		0.47
Varity_R		0.19
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35430888; hg19: chr20-62059752;