rs781375160

chr9-135770378-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_020822.3(KCNT1):c.1700G>T(p.Gly567Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.88

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22177789).
• BP6: Variant 9-135770378-G-T is Benign according to our data. Variant chr9-135770378-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540573.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.1700G>T	p.Gly567Val	missense_variant	17/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.1700G>T	p.Gly567Val	missense_variant	17/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250658 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460954 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726836

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
REVEL	Benign	0.079
Sift4G	Benign	0.070	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0060	.;.;.;.;.;.;.;.;B;.
Vest4		0.47
MutPred		0.53		.;.;.;.;.;.;Loss of catalytic residue at G548 (P = 0.0233);Loss of catalytic residue at G548 (P = 0.0233);Loss of catalytic residue at G548 (P = 0.0233);Loss of catalytic residue at G548 (P = 0.0233);
MVP		0.48
MPC		0.81
ClinPred		0.50	T
GERP RS		1.5
Varity_R		0.33
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs781375160; hg19: chr9-138662224;