NM_172107.4:c.2279G>A

Variant names:

• chr20-63406984-C-T
• rs758530960
• NM_172107.4:c.2279G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_172107.4(KCNQ2):​c.2279G>A​(p.Arg760His) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,521,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 4.38

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 Likely_benign. Variant got -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.2279G>A	p.Arg760His	missense_variant	Exon 17 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.2279G>A	p.Arg760His	missense_variant	Exon 17 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000657 AC: 8 AN: 121808 Hom.: 0 AF XY: 0.0000602 AC XY: 4 AN XY: 66412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000834

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000955

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000664

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 31 AN: 1369690 Hom.: 0 Cov.: 36 AF XY: 0.0000208 AC XY: 14 AN XY: 673986

Gnomad4 AFR exome AF: 0.0000319

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.0000259

Gnomad4 FIN exome AF: 0.0000571

Gnomad4 NFE exome AF: 0.0000215

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000634 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ2 c.2279G>A (p.Arg760His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 121808 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2279G>A in individuals affected with KCNQ2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 216827). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Aug 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 760 of the KCNQ2 protein (p.Arg760His). This variant is present in population databases (rs758530960, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 216827). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect KCNQ2 function (PMID: 35104249). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Jan 02, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Complex neurodevelopmental disorder Other:1

-

Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	.;T;T;T;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	.;.;M;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	.;.;N;.;N;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.010	.;.;D;.;D;.
Sift4G	Benign	0.11	T;.;T;T;T;T
Polyphen		0.99	D;.;D;.;D;D
Vest4		0.39
MutPred		0.39		.;.;Loss of methylation at R760 (P = 0.0215);.;.;.;
MVP		0.75
MPC		1.8
ClinPred		0.21	T
GERP RS		5.0
Varity_R		0.18
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs758530960; hg19: chr20-62038337;