9-135784540-C-A

Variant names:

• chr9-135784540-C-A
• rs764574987
• NM_020822.3:c.2949C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000371757.7(KCNT1):​c.2949C>A​(p.Phe983Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,181,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F983F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: KCNT1 ENST00000371757.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.238
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371757.7. 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.2949C>A	p.Phe983Leu	missense	Exon 26 of 31	NP_065873.2
	KCNT1	NM_001272003.2		c.2814C>A	p.Phe938Leu	missense	Exon 25 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.2949C>A	p.Phe983Leu	missense	Exon 26 of 31	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2559C>A		non_coding_transcript_exon	Exon 26 of 32	ENSP00000418777.1
	KCNT1	ENST00000460750.5	TSL:1	n.*2559C>A		3_prime_UTR	Exon 26 of 32	ENSP00000418777.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000254 AC: 3 AN: 1181490 Hom.: 0 Cov.: 30 AF XY: 0.00000513 AC XY: 3 AN XY: 584338

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26146

American (AMR) AF: 0.00 AC: 0 AN: 33454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17560

East Asian (EAS) AF: 0.0000882 AC: 2 AN: 22674

South Asian (SAS) AF: 0.00 AC: 0 AN: 78502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3016

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 921256

Other (OTH) AF: 0.00 AC: 0 AN: 44806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.015
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.24
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.98
MutPred		0.69		Gain of catalytic residue at F964 (P = 0.0767)
MVP		0.78
MPC		1.1
ClinPred		0.99	D
GERP RS		-0.10
Varity_R		0.53
gMVP		0.97
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs764574987; hg19: chr9-138676386;