9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC

Variant names:

• chr9-135784482-G-GCTCCCTCCCTCC
• rs55843930
• NM_020822.3:c.2944-18_2944-7dupCCCTCCCTCCCT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_020822.3(KCNT1):​c.2944-18_2944-7dupCCCTCCCTCCCT 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.2944-18_2944-7dupCCCTCCCTCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-18_2809-7dupCCCTCCCTCCCT		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.2944-18_2944-7dupCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-18_*2554-7dupCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-18_2944-7dupCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 70 AN: 67738 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00226

Gnomad ASJ AF: 0.000914

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00176

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000952

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00239 AC: 939 AN: 392978 Hom.: 1 Cov.: 0 AF XY: 0.00224 AC XY: 467 AN XY: 208808

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00315 AC: 36 AN: 11422

American (AMR) AF: 0.000774 AC: 18 AN: 23260

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 37 AN: 14006

East Asian (EAS) AF: 0.00451 AC: 105 AN: 23282

South Asian (SAS) AF: 0.000152 AC: 7 AN: 46176

European-Finnish (FIN) AF: 0.00164 AC: 49 AN: 29820

Middle Eastern (MID) AF: 0.00115 AC: 2 AN: 1736

European-Non Finnish (NFE) AF: 0.00277 AC: 614 AN: 221332

Other (OTH) AF: 0.00324 AC: 71 AN: 21944

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00103 AC: 70 AN: 67798 Hom.: 0 Cov.: 0 AF XY: 0.00108 AC XY: 34 AN XY: 31396

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000643 AC: 10 AN: 15544

American (AMR) AF: 0.00226 AC: 16 AN: 7092

Ashkenazi Jewish (ASJ) AF: 0.000914 AC: 2 AN: 2188

East Asian (EAS) AF: 0.00 AC: 0 AN: 1912

South Asian (SAS) AF: 0.00176 AC: 3 AN: 1702

European-Finnish (FIN) AF: 0.00181 AC: 6 AN: 3312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.000953 AC: 33 AN: 34642

Other (OTH) AF: 0.00 AC: 0 AN: 892

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16

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;