rs532620254

Positions:

• chr9-135771014-C-G
• chr9-135771014-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020822.3(KCNT1):​c.1927C>G​(p.Arg643Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R643Q) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.75

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13481876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.1927C>G	p.Arg643Gly	missense_variant	18/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.1927C>G	p.Arg643Gly	missense_variant	18/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248784 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134928

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152308 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74468

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	.;.;.;.;.;.;.;.;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	.;.;.;.;.;.;.;.;L;.
MutationTaster	Benign	0.56	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.54	.;.;N;N;.;.;.;.;N;N
REVEL	Benign	0.058
Sift	Benign	0.086	.;.;T;T;.;.;.;.;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020	.;.;.;.;.;.;.;.;B;.
Vest4		0.30
MutPred		0.35		.;.;.;.;.;.;Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);
MVP		0.40
MPC		0.82
ClinPred		0.63	D
GERP RS		3.9
Varity_R		0.24
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs532620254; hg19: chr9-138662860;