1-196228333-T-C

Position:

• chr1-196228333-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198503.5(KCNT2):​c.3299A>G​(p.Tyr1100Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000706 in 1,415,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KCNT2 NM_198503.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT2	NM_198503.5	c.3299A>G	p.Tyr1100Cys	missense_variant, splice_region_variant	28/28	ENST00000294725.14	NP_940905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT2	ENST00000294725.14	c.3299A>G	p.Tyr1100Cys	missense_variant, splice_region_variant	28/28	1	NM_198503.5	ENSP00000294725.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1415578 Hom.: 0 Cov.: 24 AF XY: 0.00000142 AC XY: 1 AN XY: 706626

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: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.4	.;.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.9	D;.;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.85
MutPred		0.63		.;.;Loss of phosphorylation at Y1100 (P = 0.0304);
MVP		0.19
MPC		1.4
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.85

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: rs1653651798; hg19: chr1-196197463;