1-196280852-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198503.5(KCNT2):c.2910+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,610,636 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: KCNT2 NM_198503.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001156
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.830

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-196280852-T-C is Benign according to our data. Variant chr1-196280852-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2639676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000821 (125/152344) while in subpopulation SAS AF= 0.00124 (6/4828). AF 95% confidence interval is 0.000941. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 125 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT2	NM_198503.5	c.2910+8A>G		splice_region_variant, intron_variant		ENST00000294725.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT2	ENST00000294725.14	c.2910+8A>G		splice_region_variant, intron_variant		1	NM_198503.5	P4

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000789 AC: 198 AN: 250890 Hom.: 0 AF XY: 0.000818 AC XY: 111 AN XY: 135654

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00133 AC: 1941 AN: 1458292 Hom.: 1 Cov.: 28 AF XY: 0.00129 AC XY: 939 AN XY: 725708

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000847

Gnomad4 FIN exome AF: 0.000716

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.000796

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74492

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000818 Hom.: 0

Bravo AF: 0.000710

EpiCase AF: 0.00104

EpiControl AF: 0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

KCNT2: BP4, BS1 -

KCNT2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.6
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs185228317; hg19: chr1-196249982;