9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCCCTCC

Variant names:

• chr9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCC-G
• rs55843930
• NM_020822.3:c.2944-30_2944-7delCCCTCCCTCCCTCCCTCCCTCCCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_020822.3(KCNT1):​c.2944-30_2944-7delCCCTCCCTCCCTCCCTCCCTCCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 393,236 control chromosomes in the GnomAD database, including 7 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCC-G is Benign according to our data. Variant chr9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 288487.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00188 (739/393236) while in subpopulation AFR AF = 0.0211 (241/11428). AF 95% confidence interval is 0.0189. There are 7 homozygotes in GnomAdExome4. There are 383 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 739 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.2944-30_2944-7delCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-30_2809-7delCCCTCCCTCCCTCCCTCCCTCCCT		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.2944-30_2944-7delCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-30_*2554-7delCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-30_2944-7delCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 620 AN: 67764 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00212

Gnomad ASJ AF: 0.000914

Gnomad EAS AF: 0.00518

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.000302

Gnomad MID AF: 0.00769

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00337

GnomAD4 exome AF: 0.00188 AC: 739 AN: 393236 Hom.: 7 AF XY: 0.00183 AC XY: 383 AN XY: 208924

African (AFR) AF: 0.0211 AC: 241 AN: 11428

American (AMR) AF: 0.00236 AC: 55 AN: 23260

Ashkenazi Jewish (ASJ) AF: 0.000644 AC: 9 AN: 13972

East Asian (EAS) AF: 0.000943 AC: 22 AN: 23340

South Asian (SAS) AF: 0.00178 AC: 82 AN: 46142

European-Finnish (FIN) AF: 0.000570 AC: 17 AN: 29820

Middle Eastern (MID) AF: 0.00173 AC: 3 AN: 1732

European-Non Finnish (NFE) AF: 0.00121 AC: 268 AN: 221588

Other (OTH) AF: 0.00191 AC: 42 AN: 21954

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00914 AC: 620 AN: 67824 Hom.: 12 Cov.: 0 AF XY: 0.00945 AC XY: 297 AN XY: 31412

African (AFR) AF: 0.0336 AC: 522 AN: 15552

American (AMR) AF: 0.00212 AC: 15 AN: 7092

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

East Asian (EAS) AF: 0.00522 AC: 10 AN: 1916

South Asian (SAS) AF: 0.00352 AC: 6 AN: 1704

European-Finnish (FIN) AF: 0.000302 AC: 1 AN: 3312

Middle Eastern (MID) AF: 0.00820 AC: 1 AN: 122

European-Non Finnish (NFE) AF: 0.00173 AC: 60 AN: 34650

Other (OTH) AF: 0.00335 AC: 3 AN: 896

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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;