9-135757376-A-G

Variant names:

• chr9-135757376-A-G
• NM_020822.3:c.754A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020822.3(KCNT1):​c.754A>G​(p.Met252Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.754A>G	p.Met252Val	missense_variant	Exon 9 of 31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.754A>G	p.Met252Val	missense_variant	Exon 9 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456220 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 724720

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;.;.;.;.;.;.;.;.;T;.
Eigen	Benign	0.078
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	.;.;D;D;D;.;.;.;.;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0080	.;.;D;D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.0030	.;.;.;.;.;.;.;.;.;B;.
Vest4		0.89
MutPred		0.54		.;.;.;.;.;.;.;Loss of stability (P = 0.0605);Loss of stability (P = 0.0605);Loss of stability (P = 0.0605);Loss of stability (P = 0.0605);
MVP		0.80
MPC		0.65
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.67
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-138649222;