chr1-196429676-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 236299.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT2	NM_198503.5	c.720T>A	p.Phe240Leu	missense_variant	Exon 9 of 28	ENST00000294725.14	NP_940905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT2	ENST00000294725.14	c.720T>A	p.Phe240Leu	missense_variant	Exon 9 of 28	1	NM_198503.5	ENSP00000294725.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 57 Pathogenic:1

Dec 04, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

KCNT2-related disorder Pathogenic:1

Jun 15, 2016

Sydney Children's Hospital, SCHN

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The affected residue is highly conserved to C.elegans and predicted to be pathogenic using Polyphen, SIFT and CADD (CADD score 25.5, v1.3). It is not present in the ExAC database (accessed July June 2016). At the structural level, the residue Phe-240 has been demonstrated as critical to normal Slick channel gating. The clinical condition is similar to that caused by pathogenic variants in an equivalent functional domain in the related gene KCNT1. -

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.16	N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;.;D
REVEL	Benign	0.25
Sift	Uncertain	0.026	D;.;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.52	P;B;P
Vest4		0.96
MutPred		0.44		Loss of catalytic residue at F240 (P = 0.0357);Loss of catalytic residue at F240 (P = 0.0357);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

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: rs1060499537; hg19: chr1-196398806;