NM_198503.5:c.3316C>T

Variant names:

• chr1-196228316-G-A
• rs1488088605
• NM_198503.5:c.3316C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_198503.5(KCNT2):​c.3316C>T​(p.Pro1106Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,450,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KCNT2 NM_198503.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41254967).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

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.3316C>T	p.Pro1106Ser	missense	Exon 28 of 28	NP_940905.2
	KCNT2	NM_001287819.3		c.3244C>T	p.Pro1082Ser	missense	Exon 27 of 27	NP_001274748.1	Q6UVM3-2
	KCNT2	NM_001287820.3		c.3115C>T	p.Pro1039Ser	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.3316C>T	p.Pro1106Ser	missense	Exon 28 of 28	ENSP00000294725.8	Q6UVM3-1
	KCNT2	ENST00000367433.9	TSL:1	c.3244C>T	p.Pro1082Ser	missense	Exon 27 of 27	ENSP00000356403.5	Q6UVM3-2
	KCNT2	ENST00000609185.5	TSL:1	c.3115C>T	p.Pro1039Ser	missense	Exon 27 of 27	ENSP00000476657.1	Q6UVM3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248690 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000591

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: 0.00000620 AC: 9 AN: 1450538 Hom.: 0 Cov.: 27 AF XY: 0.00000415 AC XY: 3 AN XY: 722324

African (AFR) AF: 0.00 AC: 0 AN: 33104

American (AMR) AF: 0.000203 AC: 9 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103012

Other (OTH) AF: 0.00 AC: 0 AN: 59950

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.56
MutPred		0.41		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.12
MPC		0.94
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.31
gMVP		0.69
Mutation Taster		=49/51	disease causing

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: rs1488088605; hg19: chr1-196197446; COSMIC: COSV104593158;