9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCC-GCTCCCTCCCTCC

Variant names:

• chr9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCC-G
• rs55843930
• NM_020822.3:c.2944-34_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020822.3(KCNT1):​c.2944-34_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 393,590 control chromosomes in the GnomAD database, including 569 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 0.022 (63 hom., cov: 0)
  • Exomes 𝑓: 0.021 (569 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:4
• 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 -16 ACMG points.

• BP6: Variant 9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCC-G is Benign according to our data. Variant chr9-135784482-GCTCCCTCCCTCCCTCCCTCCCTCCCTCC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 288488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

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.2944-34_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.2809-34_2809-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCT		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.2944-34_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-34_*2554-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.2944-34_2944-7delCCCTCCCTCCCTCCCTCCCTCCCTCCCT		splice_region intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 1489 AN: 67768 Hom.: 62 Cov.: 0

Gnomad AFR AF: 0.00814

Gnomad AMI AF: 0.0587

Gnomad AMR AF: 0.0697

Gnomad ASJ AF: 0.00640

Gnomad EAS AF: 0.0922

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.00634

Gnomad MID AF: 0.00769

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0315

GnomAD4 exome AF: 0.0207 AC: 8147 AN: 393590 Hom.: 569 AF XY: 0.0227 AC XY: 4755 AN XY: 209112

African (AFR) AF: 0.00446 AC: 51 AN: 11432

American (AMR) AF: 0.0764 AC: 1779 AN: 23272

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 49 AN: 14026

East Asian (EAS) AF: 0.0485 AC: 1132 AN: 23338

South Asian (SAS) AF: 0.0623 AC: 2878 AN: 46190

European-Finnish (FIN) AF: 0.00419 AC: 125 AN: 29852

Middle Eastern (MID) AF: 0.00805 AC: 14 AN: 1740

European-Non Finnish (NFE) AF: 0.00783 AC: 1737 AN: 221756

Other (OTH) AF: 0.0174 AC: 382 AN: 21984

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0220 AC: 1494 AN: 67828 Hom.: 63 Cov.: 0 AF XY: 0.0244 AC XY: 766 AN XY: 31412

African (AFR) AF: 0.00810 AC: 126 AN: 15550

American (AMR) AF: 0.0701 AC: 497 AN: 7094

Ashkenazi Jewish (ASJ) AF: 0.00640 AC: 14 AN: 2188

East Asian (EAS) AF: 0.0924 AC: 177 AN: 1916

South Asian (SAS) AF: 0.118 AC: 200 AN: 1702

European-Finnish (FIN) AF: 0.00634 AC: 21 AN: 3312

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

European-Non Finnish (NFE) AF: 0.0117 AC: 406 AN: 34656

Other (OTH) AF: 0.0324 AC: 29 AN: 896

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
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Developmental and epileptic encephalopathy, 14 (1)
-	-	1	not provided (1)
-	-	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;