9-135714735-CG-CGGG

Variant names:

• chr9-135714735-C-CGG
• rs141291153
• NM_020822.3:c.254+18_254+19dupGG

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.254+18_254+19dupGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,344,286 control chromosomes in the GnomAD database, including 36,993 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6258 hom., cov: 21)
  • Exomes 𝑓: 0.22 (30735 hom.)
• Consequence: KCNT1 NM_020822.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.114
• Publications: 2 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, G2P, Labcorp Genetics (formerly Invitae)
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• 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 9-135714735-C-CGG is Benign according to our data. Variant chr9-135714735-C-CGG is described in ClinVar as Benign. ClinVar VariationId is 261362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 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.254+18_254+19dupGG		intron	N/A	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.110+12370_110+12371dupGG		intron	N/A	NP_001258932.1	Q5JUK3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.254+18_254+19dupGG		intron	N/A	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.254+18_254+19dupGG		intron	N/A	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000487664.5	TSL:5	c.254+18_254+19dupGG		intron	N/A	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes AF: 0.277 AC: 41440 AN: 149590 Hom.: 6241 Cov.: 21

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.208 AC: 19562 AN: 94148 AF XY: 0.213

Gnomad AFR exome AF: 0.354

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.215

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.219 AC: 261221 AN: 1194588 Hom.: 30735 Cov.: 30 AF XY: 0.219 AC XY: 128745 AN XY: 587644

African (AFR) AF: 0.392 AC: 9205 AN: 23494

American (AMR) AF: 0.205 AC: 4530 AN: 22126

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 3230 AN: 17136

East Asian (EAS) AF: 0.161 AC: 3649 AN: 22662

South Asian (SAS) AF: 0.288 AC: 16983 AN: 58908

European-Finnish (FIN) AF: 0.180 AC: 6399 AN: 35532

Middle Eastern (MID) AF: 0.189 AC: 797 AN: 4228

European-Non Finnish (NFE) AF: 0.214 AC: 206588 AN: 965166

Other (OTH) AF: 0.217 AC: 9840 AN: 45336

GnomAD4 genome AF: 0.277 AC: 41504 AN: 149698 Hom.: 6258 Cov.: 21 AF XY: 0.274 AC XY: 20049 AN XY: 73042

African (AFR) AF: 0.408 AC: 16741 AN: 41038

American (AMR) AF: 0.240 AC: 3611 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 717 AN: 3434

East Asian (EAS) AF: 0.263 AC: 1345 AN: 5108

South Asian (SAS) AF: 0.317 AC: 1523 AN: 4804

European-Finnish (FIN) AF: 0.198 AC: 1948 AN: 9858

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.221 AC: 14803 AN: 67128

Other (OTH) AF: 0.255 AC: 528 AN: 2070

Alfa AF: 0.250 Hom.: 491

Asia WGS AF: 0.248 AC: 802 AN: 3230

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Developmental and epileptic encephalopathy, 14 (1)
-	-	1	Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
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: rs141291153; hg19: chr9-138606581; COSMIC: COSV53703908; COSMIC: COSV53703908;