9-135786170-CGCCCTGCCCTGCCCT-CGCCCTGCCCTGCCCTGCCCT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.3178-7_3178-3dupTGCCC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0063 (23 hom.)
• Consequence: KCNT1 NM_020822.3 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.600
• 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 -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BP6: Variant 9-135786170-C-CGCCCT is Benign according to our data. Variant chr9-135786170-C-CGCCCT is described in ClinVar as Benign. ClinVar VariationId is 196185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00574 (865/150638) while in subpopulation AMR AF = 0.00868 (132/15210). AF 95% confidence interval is 0.00747. There are 3 homozygotes in GnomAd4. There are 411 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 865 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.3178-7_3178-3dupTGCCC		splice_acceptor intron	N/A	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.3043-7_3043-3dupTGCCC		splice_acceptor 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_3178-3dupTGCCC		splice_acceptor intron	N/A	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*2788-7_*2788-3dupTGCCC		splice_acceptor intron	N/A	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000487664.5	TSL:5	c.3178-7_3178-3dupTGCCC		splice_acceptor intron	N/A	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 865 AN: 150524 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00869

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00413

Gnomad SAS AF: 0.00253

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00736

Gnomad OTH AF: 0.00727

GnomAD2 exomes AF: 0.00488 AC: 962 AN: 197052 AF XY: 0.00464

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.00331

Gnomad EAS exome AF: 0.00414

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00601

Gnomad OTH exome AF: 0.00593

GnomAD4 exome AF: 0.00634 AC: 8863 AN: 1397248 Hom.: 23 Cov.: 12 AF XY: 0.00629 AC XY: 4377 AN XY: 696296

African (AFR) AF: 0.00324 AC: 99 AN: 30558

American (AMR) AF: 0.00708 AC: 275 AN: 38858

Ashkenazi Jewish (ASJ) AF: 0.00350 AC: 88 AN: 25144

East Asian (EAS) AF: 0.00417 AC: 161 AN: 38610

South Asian (SAS) AF: 0.00314 AC: 257 AN: 81932

European-Finnish (FIN) AF: 0.00333 AC: 168 AN: 50462

Middle Eastern (MID) AF: 0.00322 AC: 18 AN: 5596

European-Non Finnish (NFE) AF: 0.00695 AC: 7428 AN: 1068114

Other (OTH) AF: 0.00636 AC: 369 AN: 57974

GnomAD4 genome AF: 0.00574 AC: 865 AN: 150638 Hom.: 3 Cov.: 0 AF XY: 0.00559 AC XY: 411 AN XY: 73584

African (AFR) AF: 0.00334 AC: 136 AN: 40752

American (AMR) AF: 0.00868 AC: 132 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3466

East Asian (EAS) AF: 0.00414 AC: 21 AN: 5068

South Asian (SAS) AF: 0.00253 AC: 12 AN: 4744

European-Finnish (FIN) AF: 0.00315 AC: 33 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00736 AC: 498 AN: 67646

Other (OTH) AF: 0.00719 AC: 15 AN: 2086

Alfa AF: 0.00360 Hom.: 365

Bravo AF: 0.00608

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism

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;