rs149028586

Variant names:

• chr9-135777364-C-T
• rs149028586
• NM_020822.3:c.2376C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020822.3(KCNT1):​c.2376C>T​(p.Asp792Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,613,998 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (29 hom.)
• Consequence: KCNT1 NM_020822.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.54
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-135777364-C-T is Benign according to our data. Variant chr9-135777364-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00354 (539/152342) while in subpopulation AMR AF = 0.00614 (94/15310). AF 95% confidence interval is 0.00514. There are 0 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 539 AD gene.

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.2376C>T	p.Asp792Asp	synonymous	Exon 21 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.2241C>T	p.Asp747Asp	synonymous	Exon 20 of 31	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.2376C>T	p.Asp792Asp	synonymous	Exon 21 of 31	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*1986C>T		non_coding_transcript_exon	Exon 21 of 32	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000460750.5	TSL:1	n.*1986C>T		3_prime_UTR	Exon 21 of 32	ENSP00000418777.1	F8WC49

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00467

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00390 AC: 980 AN: 251142 AF XY: 0.00408

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00927

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00513

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00473 AC: 6913 AN: 1461656 Hom.: 29 Cov.: 30 AF XY: 0.00465 AC XY: 3381 AN XY: 727150

African (AFR) AF: 0.00102 AC: 34 AN: 33476

American (AMR) AF: 0.00541 AC: 242 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00938 AC: 245 AN: 26114

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.00231 AC: 199 AN: 86240

European-Finnish (FIN) AF: 0.000786 AC: 42 AN: 53406

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.00518 AC: 5755 AN: 1111880

Other (OTH) AF: 0.00595 AC: 359 AN: 60372

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00320 AC XY: 238 AN XY: 74488

African (AFR) AF: 0.00156 AC: 65 AN: 41570

American (AMR) AF: 0.00614 AC: 94 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.00103 AC: 11 AN: 10632

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00467 AC: 318 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00477 Hom.: 2

Bravo AF: 0.00414

EpiCase AF: 0.00513

EpiControl AF: 0.00564

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	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)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149028586; hg19: chr9-138669210; COSMIC: COSV53702057; COSMIC: COSV53702057;