9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCCCTCCCTCC

Variant names:

• chr9-135784482-GCTCCCTCCCTCCCTCCCTCC-G
• rs55843930
• NM_020822.3:c.2944-26_2944-7delCCCTCCCTCCCTCCCTCCCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_020822.3(KCNT1):​c.2944-26_2944-7delCCCTCCCTCCCTCCCTCCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (523 hom., cov: 0)
  • Exomes 𝑓: 0.10 (2098 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.81
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• 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.

• BP6: Variant 9-135784482-GCTCCCTCCCTCCCTCCCTCC-G is Benign according to our data. Variant chr9-135784482-GCTCCCTCCCTCCCTCCCTCC-G is described in ClinVar as Benign. ClinVar VariationId is 195980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2944-26_2944-7delCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-26_2809-7delCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	NP_001258932.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.2944-26_2944-7delCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-26_*2554-7delCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-26_2944-7delCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.138 AC: 9351 AN: 67836 Hom.: 524 Cov.: 0

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0845

Gnomad MID AF: 0.308

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.103 AC: 40468 AN: 392740 Hom.: 2098 AF XY: 0.102 AC XY: 21309 AN XY: 208668

African (AFR) AF: 0.0444 AC: 507 AN: 11420

American (AMR) AF: 0.0778 AC: 1804 AN: 23200

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 3036 AN: 13978

East Asian (EAS) AF: 0.0203 AC: 473 AN: 23334

South Asian (SAS) AF: 0.0815 AC: 3752 AN: 46056

European-Finnish (FIN) AF: 0.0842 AC: 2510 AN: 29816

Middle Eastern (MID) AF: 0.153 AC: 266 AN: 1734

European-Non Finnish (NFE) AF: 0.116 AC: 25699 AN: 221264

Other (OTH) AF: 0.110 AC: 2421 AN: 21938

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.138 AC: 9350 AN: 67896 Hom.: 523 Cov.: 0 AF XY: 0.136 AC XY: 4281 AN XY: 31454

African (AFR) AF: 0.0719 AC: 1119 AN: 15554

American (AMR) AF: 0.156 AC: 1106 AN: 7096

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 647 AN: 2190

East Asian (EAS) AF: 0.0334 AC: 64 AN: 1918

South Asian (SAS) AF: 0.126 AC: 214 AN: 1702

European-Finnish (FIN) AF: 0.0845 AC: 281 AN: 3324

Middle Eastern (MID) AF: 0.303 AC: 37 AN: 122

European-Non Finnish (NFE) AF: 0.164 AC: 5675 AN: 34702

Other (OTH) AF: 0.163 AC: 146 AN: 896

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

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	KCNT1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
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: rs55843930; hg19: chr9-138676328;