rs764574987

chr9-135784540-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_020822.3(KCNT1):c.2949C>T(p.Phe983=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,312,174 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: 𝑓 0.000046 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: KCNT1 NM_020822.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.238

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 9-135784540-C-T is Benign according to our data. Variant chr9-135784540-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 386464.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.238 with no splicing effect.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.2949C>T	p.Phe983=	synonymous_variant	26/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.2949C>T	p.Phe983=	synonymous_variant	26/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.0000459 AC: 6 AN: 130678 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000529

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000316

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000442 AC: 8 AN: 181064 Hom.: 0 AF XY: 0.0000306 AC XY: 3 AN XY: 97938

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000721

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000404

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000262 AC: 31 AN: 1181496 Hom.: 0 Cov.: 30 AF XY: 0.0000222 AC XY: 13 AN XY: 584340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000441

Gnomad4 SAS exome AF: 0.000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000174

Gnomad4 OTH exome AF: 0.0000223

GnomAD4 genome AF: 0.0000459 AC: 6 AN: 130678 Hom.: 0 Cov.: 28 AF XY: 0.0000486 AC XY: 3 AN XY: 61746

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000174

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000529

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000316

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 16, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	14
Dann	Benign	0.81

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

LitVar

Other links and lift over

dbSNP: rs764574987; hg19: chr9-138676386; COSMIC: COSV53694857; COSMIC: COSV53694857;