1-196258350-G-A

Position:

• chr1-196258350-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1 PM2 PP5_Moderate BS2

The NM_198503.5(KCNT2):​c.3055C>T​(p.Arg1019*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KCNT2 NM_198503.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.61

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-196258350-G-A is Pathogenic according to our data. Variant chr1-196258350-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2444068.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT2	NM_198503.5	c.3055C>T	p.Arg1019*	stop_gained	26/28	ENST00000294725.14	NP_940905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT2	ENST00000294725.14	c.3055C>T	p.Arg1019*	stop_gained	26/28	1	NM_198503.5	ENSP00000294725.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 57 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.37
GERP RS		4.8

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: rs1035700995; hg19: chr1-196227480; COSMIC: COSV54066014;