9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCC

Variant names:

• chr9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-G
• rs55843930
• NM_020822.3:c.2944-38_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_020822.3(KCNT1):​c.2944-38_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 461,206 control chromosomes in the GnomAD database, including 15 homozygotes. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00027 (15 hom.)
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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.

• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000274 (108/393446) while in subpopulation NFE AF = 0.000352 (78/221710). AF 95% confidence interval is 0.000288. There are 15 homozygotes in GnomAdExome4. There are 66 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 108 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.2944-38_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-38_2809-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		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.2944-38_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-38_*2554-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-38_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.0000590 AC: 4 AN: 67760 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000577

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000274 AC: 108 AN: 393446 Hom.: 15 AF XY: 0.000316 AC XY: 66 AN XY: 209032

African (AFR) AF: 0.000263 AC: 3 AN: 11418

American (AMR) AF: 0.000215 AC: 5 AN: 23206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14024

East Asian (EAS) AF: 0.000214 AC: 5 AN: 23332

South Asian (SAS) AF: 0.000217 AC: 10 AN: 46178

European-Finnish (FIN) AF: 0.0000335 AC: 1 AN: 29860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1740

European-Non Finnish (NFE) AF: 0.000352 AC: 78 AN: 221710

Other (OTH) AF: 0.000273 AC: 6 AN: 21978

GnomAD4 genome AF: 0.0000590 AC: 4 AN: 67760 Hom.: 0 Cov.: 0 AF XY: 0.0000319 AC XY: 1 AN XY: 31358

African (AFR) AF: 0.000129 AC: 2 AN: 15474

American (AMR) AF: 0.00 AC: 0 AN: 7082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2188

East Asian (EAS) AF: 0.00 AC: 0 AN: 1930

South Asian (SAS) AF: 0.00 AC: 0 AN: 1706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 130

European-Non Finnish (NFE) AF: 0.0000577 AC: 2 AN: 34656

Other (OTH) AF: 0.00 AC: 0 AN: 890

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

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;