9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC

Variant names:

• chr9-135784482-G-GCTCC
• rs55843930
• NM_020822.3:c.2944-10_2944-7dupCCCT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_020822.3(KCNT1):​c.2944-10_2944-7dupCCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.035 (19 hom., cov: 0)
  • Exomes 𝑓: 0.047 (187 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 9-135784482-G-GCTCC is Benign according to our data. Variant chr9-135784482-G-GCTCC is described in ClinVar as Benign. ClinVar VariationId is 3038164.Status of the report is no_assertion_criteria_provided, 0 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.2944-10_2944-7dupCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-10_2809-7dupCCCT		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.2944-10_2944-7dupCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-10_*2554-7dupCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-10_2944-7dupCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 2326 AN: 67098 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.0155

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.0568

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.0308

Gnomad NFE AF: 0.0345

Gnomad OTH AF: 0.0421

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0469 AC: 18125 AN: 386440 Hom.: 187 Cov.: 0 AF XY: 0.0455 AC XY: 9333 AN XY: 205216

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

African (AFR) AF: 0.0483 AC: 545 AN: 11288

American (AMR) AF: 0.0245 AC: 564 AN: 23004

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 487 AN: 13864

East Asian (EAS) AF: 0.0835 AC: 1906 AN: 22836

South Asian (SAS) AF: 0.0180 AC: 814 AN: 45148

European-Finnish (FIN) AF: 0.0428 AC: 1259 AN: 29438

Middle Eastern (MID) AF: 0.0398 AC: 68 AN: 1710

European-Non Finnish (NFE) AF: 0.0520 AC: 11316 AN: 217584

Other (OTH) AF: 0.0541 AC: 1166 AN: 21568

⚠️ 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: 0.0347 AC: 2327 AN: 67156 Hom.: 19 Cov.: 0 AF XY: 0.0357 AC XY: 1110 AN XY: 31114

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

African (AFR) AF: 0.0310 AC: 477 AN: 15398

American (AMR) AF: 0.0340 AC: 238 AN: 7002

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 44 AN: 2174

East Asian (EAS) AF: 0.0551 AC: 104 AN: 1886

South Asian (SAS) AF: 0.0533 AC: 89 AN: 1670

European-Finnish (FIN) AF: 0.0437 AC: 144 AN: 3296

Middle Eastern (MID) AF: 0.0328 AC: 4 AN: 122

European-Non Finnish (NFE) AF: 0.0345 AC: 1184 AN: 34336

Other (OTH) AF: 0.0419 AC: 37 AN: 884

⚠️ 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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KCNT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
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;