rs117286274

chr9-135757333-C-Gchr9-135757333-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020822.3(KCNT1):c.711C>G(p.Pro237=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,611,700 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P237P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (9 hom., cov: 31)
  • Exomes 𝑓: 0.017 (278 hom.)
• Consequence: KCNT1 NM_020822.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.05

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-135757333-C-G is Benign according to our data. Variant chr9-135757333-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 129367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135757333-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1837/152108) while in subpopulation NFE AF= 0.0196 (1332/67978). AF 95% confidence interval is 0.0187. There are 9 homozygotes in gnomad4. There are 867 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1837 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.711C>G	p.Pro237=	synonymous_variant	9/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.711C>G	p.Pro237=	synonymous_variant	9/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1837 AN: 151990 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00964

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.0117 AC: 2915 AN: 249970 Hom.: 27 AF XY: 0.0116 AC XY: 1575 AN XY: 135358

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00897

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0172 AC: 25085 AN: 1459592 Hom.: 278 Cov.: 36 AF XY: 0.0166 AC XY: 12073 AN XY: 726272

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00919

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.0204

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0121 AC: 1837 AN: 152108 Hom.: 9 Cov.: 31 AF XY: 0.0117 AC XY: 867 AN XY: 74344

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00963

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00876 Hom.: 3

Bravo AF: 0.0110

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0178

EpiControl AF: 0.0165

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy, 14 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.24
Dann	Benign	0.72

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: rs117286274; hg19: chr9-138649179;