rs28612938

Variant names:

• chr9-135784131-C-T
• rs28612938
• NM_020822.3:c.2943+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.2943+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,601,074 control chromosomes in the GnomAD database, including 94 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 0.014 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (57 hom.)
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002636
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.756
• Publications: 2 publications found

Genes affected

KCNT1 (HGNC:18865): (potassium sodium-activated channel subfamily T member 1) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

KCNT1 Gene-Disease associations (from GenCC):

• childhood-onset epilepsy syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 14

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• autosomal dominant nocturnal frontal lobe epilepsy 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-135784131-C-T is Benign according to our data. Variant chr9-135784131-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (2063/152320) while in subpopulation AFR AF = 0.0401 (1668/41566). AF 95% confidence interval is 0.0385. There are 37 homozygotes in GnomAd4. There are 973 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2063 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020822.3. 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
	KCNT1	NM_020822.3	MANE Select	c.2943+6C>T		splice_region intron	N/A	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.2808+6C>T		splice_region intron	N/A	NP_001258932.1	Q5JUK3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.2943+6C>T		splice_region intron	N/A	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*2553+6C>T		splice_region intron	N/A	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000487664.5	TSL:5	c.2943+6C>T		splice_region intron	N/A	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2053 AN: 152202 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00559 AC: 1353 AN: 242072 AF XY: 0.00466

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.00917

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000144

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00743

GnomAD4 exome AF: 0.00311 AC: 4508 AN: 1448754 Hom.: 57 Cov.: 31 AF XY: 0.00300 AC XY: 2162 AN XY: 721216

African (AFR) AF: 0.0451 AC: 1507 AN: 33408

American (AMR) AF: 0.00655 AC: 293 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00877 AC: 229 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00255 AC: 220 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42238

Middle Eastern (MID) AF: 0.0288 AC: 166 AN: 5764

European-Non Finnish (NFE) AF: 0.00155 AC: 1721 AN: 1110306

Other (OTH) AF: 0.00615 AC: 371 AN: 60288

GnomAD4 genome AF: 0.0135 AC: 2063 AN: 152320 Hom.: 37 Cov.: 33 AF XY: 0.0131 AC XY: 973 AN XY: 74484

African (AFR) AF: 0.0401 AC: 1668 AN: 41566

American (AMR) AF: 0.0110 AC: 168 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 68030

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.0104 Hom.: 8

Bravo AF: 0.0156

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Developmental and epileptic encephalopathy, 14 (1)
-	-	1	Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.2
DANN	Benign	0.64
PhyloP100		-0.76
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0040
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: rs28612938; hg19: chr9-138675977;