9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC

Variant names:

• chr9-135784482-GCTCCCTCC-G
• rs55843930
• NM_020822.3:c.2944-14_2944-7delCCCTCCCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_020822.3(KCNT1):​c.2944-14_2944-7delCCCTCCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (1711 hom., cov: 0)
  • Exomes 𝑓: 0.18 (5242 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 9-135784482-GCTCCCTCC-G is Benign according to our data. Variant chr9-135784482-GCTCCCTCC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2944-14_2944-7delCCCTCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-14_2809-7delCCCTCCCT		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.2944-14_2944-7delCCCTCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-14_*2554-7delCCCTCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-14_2944-7delCCCTCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 14606 AN: 67456 Hom.: 1712 Cov.: 0

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.195

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.164

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.181 AC: 68917 AN: 380182 Hom.: 5242 AF XY: 0.177 AC XY: 35744 AN XY: 201674

African (AFR) AF: 0.155 AC: 1738 AN: 11248

American (AMR) AF: 0.0709 AC: 1611 AN: 22728

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 2058 AN: 13772

East Asian (EAS) AF: 0.190 AC: 4358 AN: 22904

South Asian (SAS) AF: 0.108 AC: 4700 AN: 43368

European-Finnish (FIN) AF: 0.173 AC: 5022 AN: 29024

Middle Eastern (MID) AF: 0.192 AC: 323 AN: 1682

European-Non Finnish (NFE) AF: 0.211 AC: 45107 AN: 214118

Other (OTH) AF: 0.187 AC: 4000 AN: 21338

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.216 AC: 14613 AN: 67520 Hom.: 1711 Cov.: 0 AF XY: 0.212 AC XY: 6640 AN XY: 31282

African (AFR) AF: 0.197 AC: 3054 AN: 15504

American (AMR) AF: 0.154 AC: 1087 AN: 7040

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 408 AN: 2174

East Asian (EAS) AF: 0.180 AC: 342 AN: 1904

South Asian (SAS) AF: 0.193 AC: 328 AN: 1702

European-Finnish (FIN) AF: 0.210 AC: 695 AN: 3308

Middle Eastern (MID) AF: 0.197 AC: 24 AN: 122

European-Non Finnish (NFE) AF: 0.245 AC: 8440 AN: 34486

Other (OTH) AF: 0.163 AC: 145 AN: 890

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Developmental and epileptic encephalopathy, 14 (1)
-	-	1	KCNT1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV53707586; COSMIC: COSV53707586;