9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_020822.3(KCNT1):​c.2944-10_2944-7delCCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (719 hom., cov: 0)
  • Exomes 𝑓: 0.12 (2854 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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 -2 ACMG points.

• BP6: Variant 9-135784482-GCTCC-G is Benign according to our data. Variant chr9-135784482-GCTCC-G is described in ClinVar as Benign. ClinVar VariationId is 195984.Status of the report is criteria_provided_single_submitter, 1 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_2944-7delCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-10_2809-7delCCCT		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_2944-7delCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-10_*2554-7delCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-10_2944-7delCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 8675 AN: 67370 Hom.: 715 Cov.: 0

Gnomad AFR AF: 0.0922

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.151

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.124 AC: 47673 AN: 383914 Hom.: 2854 AF XY: 0.121 AC XY: 24726 AN XY: 203820

African (AFR) AF: 0.0931 AC: 1049 AN: 11270

American (AMR) AF: 0.108 AC: 2451 AN: 22640

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 1577 AN: 13822

East Asian (EAS) AF: 0.202 AC: 4634 AN: 22928

South Asian (SAS) AF: 0.0614 AC: 2718 AN: 44270

European-Finnish (FIN) AF: 0.149 AC: 4349 AN: 29124

Middle Eastern (MID) AF: 0.146 AC: 248 AN: 1704

European-Non Finnish (NFE) AF: 0.128 AC: 27693 AN: 216674

Other (OTH) AF: 0.138 AC: 2954 AN: 21482

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.129 AC: 8687 AN: 67428 Hom.: 719 Cov.: 0 AF XY: 0.131 AC XY: 4088 AN XY: 31242

African (AFR) AF: 0.0926 AC: 1437 AN: 15514

American (AMR) AF: 0.184 AC: 1287 AN: 7002

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 272 AN: 2172

East Asian (EAS) AF: 0.197 AC: 371 AN: 1886

South Asian (SAS) AF: 0.116 AC: 196 AN: 1692

European-Finnish (FIN) AF: 0.177 AC: 586 AN: 3302

Middle Eastern (MID) AF: 0.123 AC: 15 AN: 122

European-Non Finnish (NFE) AF: 0.125 AC: 4307 AN: 34456

Other (OTH) AF: 0.150 AC: 134 AN: 892

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	KCNT1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55843930; hg19: chr9-138676328;