1-196258215-C-T

Variant names:

• chr1-196258215-C-T
• rs1656687729
• NM_198503.5:c.3190G>A

Variant summary

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

The NM_198503.5(KCNT2):​c.3190G>A​(p.Gly1064Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1064C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNT2 NM_198503.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3190G>A	p.Gly1064Ser	missense	Exon 26 of 28	NP_940905.2
	KCNT2	NM_001287819.3		c.3118G>A	p.Gly1040Ser	missense	Exon 25 of 27	NP_001274748.1	Q6UVM3-2
	KCNT2	NM_001287820.3		c.2989G>A	p.Gly997Ser	missense	Exon 25 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.3190G>A	p.Gly1064Ser	missense	Exon 26 of 28	ENSP00000294725.8	Q6UVM3-1
	KCNT2	ENST00000367433.9	TSL:1	c.3118G>A	p.Gly1040Ser	missense	Exon 25 of 27	ENSP00000356403.5	Q6UVM3-2
	KCNT2	ENST00000609185.5	TSL:1	c.2989G>A	p.Gly997Ser	missense	Exon 25 of 27	ENSP00000476657.1	Q6UVM3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	0.0064	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.41		Gain of relative solvent accessibility (P = 0.0522)
MVP		0.16
MPC		1.2
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.41
gMVP		0.67
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1656687729; hg19: chr1-196227345; COSMIC: COSV99653820;