1-196228244-G-C

Variant names:

• chr1-196228244-G-C
• rs188819863
• NM_198503.5:c.3388C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198503.5(KCNT2):​c.3388C>G​(p.Arg1130Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1130W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNT2 NM_198503.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

Genes affected

KCNT2 (HGNC:18866): (potassium sodium-activated channel subfamily T member 2) Enables chloride-activated potassium channel activity. Involved in potassium ion export across plasma membrane. Located in plasma membrane. Implicated in developmental and epileptic encephalopathy 57. [provided by Alliance of Genome Resources, Apr 2022]

KCNT2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 57

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20762786).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198503.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT2	NM_198503.5	MANE Select	c.3388C>G	p.Arg1130Gly	missense	Exon 28 of 28	NP_940905.2
	KCNT2	NM_001287819.3		c.3316C>G	p.Arg1106Gly	missense	Exon 27 of 27	NP_001274748.1	Q6UVM3-2
	KCNT2	NM_001287820.3		c.3187C>G	p.Arg1063Gly	missense	Exon 27 of 27	NP_001274749.1	Q6UVM3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT2	ENST00000294725.14	TSL:1 MANE Select	c.3388C>G	p.Arg1130Gly	missense	Exon 28 of 28	ENSP00000294725.8	Q6UVM3-1
	KCNT2	ENST00000367433.9	TSL:1	c.3316C>G	p.Arg1106Gly	missense	Exon 27 of 27	ENSP00000356403.5	Q6UVM3-2
	KCNT2	ENST00000609185.5	TSL:1	c.3187C>G	p.Arg1063Gly	missense	Exon 27 of 27	ENSP00000476657.1	Q6UVM3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248386 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454228 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723818

African (AFR) AF: 0.00 AC: 0 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39368

South Asian (SAS) AF: 0.00 AC: 0 AN: 85742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106450

Other (OTH) AF: 0.0000166 AC: 1 AN: 60078

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.084
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.96	D
Vest4		0.37
MutPred		0.31		Loss of helix (P = 0.0558)
MVP		0.093
MPC		1.4
ClinPred		0.94	D
GERP RS		2.6
Varity_R		0.18
gMVP		0.48
Mutation Taster		=75/25	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

Other links and lift over

dbSNP: rs188819863; hg19: chr1-196197374;