rs111647144

Variant names:

• chr9-135772764-C-A
• rs111647144
• NM_020822.3:c.2058C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-135772764-C-A
• chr9-135772764-C-G
• chr9-135772764-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020822.3(KCNT1):​c.2058C>A​(p.Ser686Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000755 in 1,324,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S686S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060134202).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	NM_020822.3	MANE Select	c.2058C>A	p.Ser686Arg	missense	Exon 19 of 31	NP_065873.2
	KCNT1	NM_001272003.2		c.1923C>A	p.Ser641Arg	missense	Exon 18 of 31	NP_001258932.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.2058C>A	p.Ser686Arg	missense	Exon 19 of 31	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*1668C>A		non_coding_transcript_exon	Exon 19 of 32	ENSP00000418777.1
	KCNT1	ENST00000460750.5	TSL:1	n.*1668C>A		3_prime_UTR	Exon 19 of 32	ENSP00000418777.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1324406 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 645482

African (AFR) AF: 0.00 AC: 0 AN: 29266

American (AMR) AF: 0.00 AC: 0 AN: 25348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20476

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 33958

South Asian (SAS) AF: 0.00 AC: 0 AN: 67132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5328

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1042918

Other (OTH) AF: 0.00 AC: 0 AN: 54790

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.9
DANN	Benign	0.56
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.039
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.0070
Sift	Benign	0.50	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.36
MutPred		0.20		Loss of glycosylation at S667 (P = 0.0067)
MVP		0.12
MPC		0.71
ClinPred		0.21	T
GERP RS		-3.3
Varity_R		0.042
gMVP		0.39
Mutation Taster		=92/8	polymorphism

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: rs111647144; hg19: chr9-138664610; COSMIC: COSV53701542; COSMIC: COSV53701542;