chr1-196601576-A-G

Variant names:

• chr1-196601576-A-G
• rs10754196
• NM_198503.5:c.95+6639T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198503.5(KCNT2):​c.95+6639T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,020 control chromosomes in the GnomAD database, including 7,028 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7028 hom., cov: 32)
• Consequence: KCNT2 NM_198503.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

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.95+6639T>C		intron	N/A	NP_940905.2
	KCNT2	NM_001287819.3		c.95+6639T>C		intron	N/A	NP_001274748.1
	KCNT2	NM_001287820.3		c.95+6639T>C		intron	N/A	NP_001274749.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT2	ENST00000294725.14	TSL:1 MANE Select	c.95+6639T>C		intron	N/A	ENSP00000294725.8
	KCNT2	ENST00000367433.9	TSL:1	c.95+6639T>C		intron	N/A	ENSP00000356403.5
	KCNT2	ENST00000609185.5	TSL:1	c.95+6639T>C		intron	N/A	ENSP00000476657.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45487 AN: 151904 Hom.: 7021 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.308

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.299 AC: 45521 AN: 152020 Hom.: 7028 Cov.: 32 AF XY: 0.304 AC XY: 22627 AN XY: 74330

African (AFR) AF: 0.235 AC: 9758 AN: 41470

American (AMR) AF: 0.395 AC: 6022 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1265 AN: 3470

East Asian (EAS) AF: 0.357 AC: 1847 AN: 5170

South Asian (SAS) AF: 0.306 AC: 1474 AN: 4824

European-Finnish (FIN) AF: 0.336 AC: 3547 AN: 10556

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20557 AN: 67952

Other (OTH) AF: 0.306 AC: 646 AN: 2110

Alfa AF: 0.300 Hom.: 5008

Bravo AF: 0.301

Asia WGS AF: 0.340 AC: 1180 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.5
DANN	Benign	0.42
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs10754196; hg19: chr1-196570706;