rs496503

Variant names:

• chr9-135705128-G-A
• rs496503
• NM_020822.3:c.110+2760G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020822.3(KCNT1):​c.110+2760G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 152,252 control chromosomes in the GnomAD database, including 57,815 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (57815 hom., cov: 33)
• Consequence: KCNT1 NM_020822.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.41
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.92 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.110+2760G>A		intron	N/A	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.110+2760G>A		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.110+2760G>A		intron	N/A	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.110+2760G>A		intron	N/A	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000487664.5	TSL:5	c.110+2760G>A		intron	N/A	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes AF: 0.868 AC: 132044 AN: 152132 Hom.: 57805 Cov.: 33

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.978

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.847

Gnomad EAS AF: 0.836

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.966

Gnomad MID AF: 0.830

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.861

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.868 AC: 132101 AN: 152252 Hom.: 57815 Cov.: 33 AF XY: 0.870 AC XY: 64790 AN XY: 74462

African (AFR) AF: 0.747 AC: 30998 AN: 41512

American (AMR) AF: 0.864 AC: 13223 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.847 AC: 2942 AN: 3472

East Asian (EAS) AF: 0.836 AC: 4318 AN: 5166

South Asian (SAS) AF: 0.911 AC: 4394 AN: 4824

European-Finnish (FIN) AF: 0.966 AC: 10260 AN: 10618

Middle Eastern (MID) AF: 0.832 AC: 243 AN: 292

European-Non Finnish (NFE) AF: 0.926 AC: 63009 AN: 68036

Other (OTH) AF: 0.861 AC: 1822 AN: 2116

Alfa AF: 0.902 Hom.: 186935

Bravo AF: 0.852

Asia WGS AF: 0.865 AC: 3010 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.39
DANN	Benign	0.45
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs496503; hg19: chr9-138596974;