chr1-196429676-A-T

Variant names:

• chr1-196429676-A-T
• rs1060499537
• NM_198503.5:c.720T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_198503.5(KCNT2):​c.720T>A​(p.Phe240Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNT2 NM_198503.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.63
• Publications: 12 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-196429676-A-T is Pathogenic according to our data. Variant chr1-196429676-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 236299.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT2	NM_198503.5	MANE Select	c.720T>A	p.Phe240Leu	missense	Exon 9 of 28	NP_940905.2
	KCNT2	NM_001287819.3		c.720T>A	p.Phe240Leu	missense	Exon 9 of 27	NP_001274748.1
	KCNT2	NM_001287820.3		c.720T>A	p.Phe240Leu	missense	Exon 9 of 27	NP_001274749.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT2	ENST00000294725.14	TSL:1 MANE Select	c.720T>A	p.Phe240Leu	missense	Exon 9 of 28	ENSP00000294725.8
	KCNT2	ENST00000367433.9	TSL:1	c.720T>A	p.Phe240Leu	missense	Exon 9 of 27	ENSP00000356403.5
	KCNT2	ENST00000609185.5	TSL:1	c.720T>A	p.Phe240Leu	missense	Exon 9 of 27	ENSP00000476657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy, 57 (1)
1	-	-	KCNT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.16	N
PhyloP100		3.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.25
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.031	D
Polyphen		0.52	P
Vest4		0.96
MutPred		0.44		Loss of catalytic residue at F240 (P = 0.0357)
MVP		0.75
MPC		2.2
ClinPred		0.99	D
GERP RS		1.5
Varity_R		0.44
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs1060499537; hg19: chr1-196398806;