9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCCCTCCCTCCCTCCCTCC

Variant names:

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

Variant summary

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

The NM_020822.3(KCNT1):​c.2944-18_2944-7delCCCTCCCTCCCT 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 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 0.10 (412 hom., cov: 0)
  • Exomes 𝑓: 0.063 (676 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:5
• 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 -8 ACMG points.

• BP6: Variant 9-135784482-GCTCCCTCCCTCC-G is Benign according to our data. Variant chr9-135784482-GCTCCCTCCCTCC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195981.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.2944-18_2944-7delCCCTCCCTCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-18_2809-7delCCCTCCCTCCCT		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_2944-7delCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-18_*2554-7delCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-18_2944-7delCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 6843 AN: 67722 Hom.: 413 Cov.: 0

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0510

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0781

Gnomad NFE AF: 0.0634

Gnomad OTH AF: 0.0890

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0629 AC: 24367 AN: 387478 Hom.: 676 AF XY: 0.0614 AC XY: 12652 AN XY: 205896

African (AFR) AF: 0.145 AC: 1639 AN: 11274

American (AMR) AF: 0.0339 AC: 781 AN: 23046

Ashkenazi Jewish (ASJ) AF: 0.0540 AC: 751 AN: 13908

East Asian (EAS) AF: 0.0733 AC: 1693 AN: 23088

South Asian (SAS) AF: 0.0554 AC: 2500 AN: 45106

European-Finnish (FIN) AF: 0.143 AC: 4197 AN: 29258

Middle Eastern (MID) AF: 0.0630 AC: 108 AN: 1714

European-Non Finnish (NFE) AF: 0.0515 AC: 11251 AN: 218446

Other (OTH) AF: 0.0669 AC: 1447 AN: 21638

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.101 AC: 6850 AN: 67784 Hom.: 412 Cov.: 0 AF XY: 0.103 AC XY: 3242 AN XY: 31410

African (AFR) AF: 0.191 AC: 2974 AN: 15548

American (AMR) AF: 0.0696 AC: 493 AN: 7086

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 158 AN: 2184

East Asian (EAS) AF: 0.115 AC: 220 AN: 1912

South Asian (SAS) AF: 0.107 AC: 181 AN: 1698

European-Finnish (FIN) AF: 0.157 AC: 520 AN: 3318

Middle Eastern (MID) AF: 0.0833 AC: 10 AN: 120

European-Non Finnish (NFE) AF: 0.0633 AC: 2193 AN: 34632

Other (OTH) AF: 0.0906 AC: 81 AN: 894

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
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;