9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCCCTCCCTCCCTCC

Variant names:

• chr9-135784482-GCTCCCTCCCTCCCTCC-G
• rs55843930
• NM_020822.3:c.2944-22_2944-7delCCCTCCCTCCCTCCCT

Variant summary

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

The NM_020822.3(KCNT1):​c.2944-22_2944-7delCCCTCCCTCCCTCCCT 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 0.021 (29 hom., cov: 0)
  • Exomes 𝑓: 0.014 (81 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-GCTCCCTCCCTCCCTCC-G is Benign according to our data. Variant chr9-135784482-GCTCCCTCCCTCCCTCC-G is described in ClinVar as Benign. ClinVar VariationId is 286875.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.2944-22_2944-7delCCCTCCCTCCCTCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-22_2809-7delCCCTCCCTCCCTCCCT		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.2944-22_2944-7delCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-22_*2554-7delCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-22_2944-7delCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 1393 AN: 67762 Hom.: 29 Cov.: 0

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0183

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.00937

Gnomad FIN AF: 0.00816

Gnomad MID AF: 0.0154

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0213

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0139 AC: 5479 AN: 392920 Hom.: 81 AF XY: 0.0139 AC XY: 2898 AN XY: 208770

African (AFR) AF: 0.0139 AC: 158 AN: 11392

American (AMR) AF: 0.00934 AC: 217 AN: 23230

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 193 AN: 14012

East Asian (EAS) AF: 0.0155 AC: 361 AN: 23324

South Asian (SAS) AF: 0.00707 AC: 326 AN: 46114

European-Finnish (FIN) AF: 0.0107 AC: 319 AN: 29720

Middle Eastern (MID) AF: 0.00806 AC: 14 AN: 1736

European-Non Finnish (NFE) AF: 0.0164 AC: 3637 AN: 221448

Other (OTH) AF: 0.0116 AC: 254 AN: 21944

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0205 AC: 1393 AN: 67822 Hom.: 29 Cov.: 0 AF XY: 0.0203 AC XY: 638 AN XY: 31414

African (AFR) AF: 0.0200 AC: 311 AN: 15548

American (AMR) AF: 0.0255 AC: 181 AN: 7086

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 40 AN: 2186

East Asian (EAS) AF: 0.0120 AC: 23 AN: 1918

South Asian (SAS) AF: 0.00939 AC: 16 AN: 1704

European-Finnish (FIN) AF: 0.00816 AC: 27 AN: 3310

Middle Eastern (MID) AF: 0.0164 AC: 2 AN: 122

European-Non Finnish (NFE) AF: 0.0223 AC: 774 AN: 34660

Other (OTH) AF: 0.0212 AC: 19 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

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;