9-135786170-CGCCCTGCCCTGCCCT-CGCCCTGCCCT

Variant names:

• chr9-135786170-CGCCCT-C
• rs757968008
• NM_020822.3:c.3178-7_3178-3delTGCCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020822.3(KCNT1):​c.3178-7_3178-3delTGCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,544,516 control chromosomes in the GnomAD database, including 46,499 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7356 hom., cov: 0)
  • Exomes 𝑓: 0.24 (39143 hom.)
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.02
• 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 -16 ACMG points.

• BP6: Variant 9-135786170-CGCCCT-C is Benign according to our data. Variant chr9-135786170-CGCCCT-C is described in ClinVar as Benign. ClinVar VariationId is 196184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 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.3178-7_3178-3delTGCCC		splice_region intron	N/A	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.3043-7_3043-3delTGCCC		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.3178-7_3178-3delTGCCC		splice_region intron	N/A	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*2788-7_*2788-3delTGCCC		splice_region intron	N/A	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000487664.5	TSL:5	c.3178-7_3178-3delTGCCC		splice_region intron	N/A	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes AF: 0.297 AC: 44648 AN: 150376 Hom.: 7328 Cov.: 0

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.285

GnomAD2 exomes AF: 0.242 AC: 47644 AN: 197052 AF XY: 0.244

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.257

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.243 AC: 338211 AN: 1394026 Hom.: 39143 AF XY: 0.244 AC XY: 169621 AN XY: 694772

African (AFR) AF: 0.433 AC: 13205 AN: 30474

American (AMR) AF: 0.197 AC: 7639 AN: 38780

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 4933 AN: 25120

East Asian (EAS) AF: 0.239 AC: 9224 AN: 38564

South Asian (SAS) AF: 0.273 AC: 22312 AN: 81806

European-Finnish (FIN) AF: 0.159 AC: 7999 AN: 50424

Middle Eastern (MID) AF: 0.249 AC: 1390 AN: 5586

European-Non Finnish (NFE) AF: 0.241 AC: 257073 AN: 1065412

Other (OTH) AF: 0.249 AC: 14436 AN: 57860

GnomAD4 genome AF: 0.297 AC: 44722 AN: 150490 Hom.: 7356 Cov.: 0 AF XY: 0.290 AC XY: 21328 AN XY: 73492

African (AFR) AF: 0.451 AC: 18339 AN: 40688

American (AMR) AF: 0.241 AC: 3656 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 713 AN: 3466

East Asian (EAS) AF: 0.254 AC: 1285 AN: 5066

South Asian (SAS) AF: 0.259 AC: 1228 AN: 4734

European-Finnish (FIN) AF: 0.147 AC: 1541 AN: 10462

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17115 AN: 67594

Other (OTH) AF: 0.282 AC: 589 AN: 2086

Alfa AF: 0.156 Hom.: 365

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs757968008; hg19: chr9-138678016;