20-63407176-G-A

Variant names:

• chr20-63407176-G-A
• rs570139975
• NM_172107.4:c.2087C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_172107.4(KCNQ2):​c.2087C>T​(p.Thr696Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000474 in 1,604,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T696T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0140

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

Our verdict: Benign. The variant received -12 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.023257107).
• BP6: Variant 20-63407176-G-A is Benign according to our data. Variant chr20-63407176-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461412.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000525 (8/152334) while in subpopulation AMR AF = 0.000261 (4/15312). AF 95% confidence interval is 0.0000887. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.2087C>T	p.Thr696Met	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.2087C>T	p.Thr696Met	missense_variant	Exon 17 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000246 AC: 57 AN: 231844 AF XY: 0.000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000468 AC: 68 AN: 1451838 Hom.: 1 Cov.: 36 AF XY: 0.0000374 AC XY: 27 AN XY: 722304

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33364

Gnomad4 AMR exome AF: 0.00122 AC: 54 AN: 44264

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26040

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39488

Gnomad4 SAS exome AF: 0.0000350 AC: 3 AN: 85672

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 46890

Gnomad4 NFE exome AF: 0.00000811 AC: 9 AN: 1110240

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60118

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74490

Gnomad4 AFR AF: 0.0000481 AC: 0.0000480977 AN: 0.0000480977

Gnomad4 AMR AF: 0.000261 AC: 0.000261233 AN: 0.000261233

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294066 AN: 0.0000294066

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000211 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000116 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Feb 06, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	4.0
DANN	Benign	0.96
DEOGEN2	Benign	0.29	.;T;T;T;T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.036	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.023	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	-0.11	.;.;.;.;.;N;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	.;.;.;N;.;N;.;N;.
REVEL	Benign	0.29
Sift	Benign	0.18	.;.;.;T;.;T;.;T;.
Sift4G	Benign	0.17	T;T;T;T;.;T;T;T;T
Polyphen		0.0040	B;.;.;.;.;B;.;B;B
Vest4		0.052
MutPred		0.15		.;.;.;.;.;Loss of glycosylation at S695 (P = 0.0661);.;.;.;
MVP		0.56
MPC		0.65
ClinPred		0.031	T
GERP RS		-4.8
Varity_R		0.021
gMVP		0.26
Mutation Taster		=100/0	polymorphism

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: rs570139975; hg19: chr20-62038529;