chr9-135772881-C-G

Position:

• chr9-135772881-C-G

Variant summary

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

The NM_020822.3(KCNT1):​c.2175C>G​(p.Cys725Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,218 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C725S) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.844

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, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.2175C>G	p.Cys725Trp	missense_variant	19/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.2175C>G	p.Cys725Trp	missense_variant	19/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;.;.;.;.;.;.;.;T;.
Eigen	Benign	0.056
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.16	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	.;.;D;.;.;.;.;.;D;D
REVEL	Uncertain	0.60
Sift	Benign	0.059	.;.;T;.;.;.;.;.;D;D
Sift4G	Uncertain	0.050	T;T;D;T;T;T;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;D;.
Vest4		0.85
MutPred		0.38		.;.;.;.;.;.;Loss of catalytic residue at P705 (P = 0.0064);Loss of catalytic residue at P705 (P = 0.0064);Loss of catalytic residue at P705 (P = 0.0064);.;
MVP		0.83
MPC		1.8
ClinPred		0.98	D
GERP RS		1.6
Varity_R		0.55
gMVP		0.79

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: rs368450848; hg19: chr9-138664727;