rs112341167

Variant names:

• chr9-135765016-G-A
• rs112341167
• NM_020822.3:c.1036-15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020822.3(KCNT1):​c.1036-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,599,926 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (66 hom., cov: 32)
  • Exomes 𝑓: 0.019 (379 hom.)
• Consequence: KCNT1 NM_020822.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.27
• Publications: 1 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=-0.86).
• BP6: Variant 9-135765016-G-A is Benign according to our data. Variant chr9-135765016-G-A is described in ClinVar as Benign. ClinVar VariationId is 261360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

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.1036-15G>A		intron	N/A	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.901-15G>A		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.1036-15G>A		intron	N/A	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*646-15G>A		intron	N/A	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000487664.5	TSL:5	c.1036-15G>A		intron	N/A	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3807 AN: 152170 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0553

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00785

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0189 AC: 4661 AN: 246050 AF XY: 0.0187

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.0465

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00336

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0195 AC: 28170 AN: 1447638 Hom.: 379 Cov.: 33 AF XY: 0.0193 AC XY: 13842 AN XY: 717150

African (AFR) AF: 0.0376 AC: 1248 AN: 33232

American (AMR) AF: 0.0205 AC: 906 AN: 44290

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 1287 AN: 25994

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39326

South Asian (SAS) AF: 0.00854 AC: 734 AN: 85930

European-Finnish (FIN) AF: 0.00348 AC: 182 AN: 52274

Middle Eastern (MID) AF: 0.0703 AC: 403 AN: 5730

European-Non Finnish (NFE) AF: 0.0199 AC: 21900 AN: 1101174

Other (OTH) AF: 0.0253 AC: 1508 AN: 59688

GnomAD4 genome AF: 0.0250 AC: 3807 AN: 152288 Hom.: 66 Cov.: 32 AF XY: 0.0241 AC XY: 1798 AN XY: 74464

African (AFR) AF: 0.0366 AC: 1522 AN: 41544

American (AMR) AF: 0.0334 AC: 511 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 192 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00765 AC: 37 AN: 4834

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10622

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0209 AC: 1420 AN: 68020

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0248 Hom.: 20

Bravo AF: 0.0279

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.17
DANN	Benign	0.52
PhyloP100		-1.3
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: rs112341167; hg19: chr9-138656862;