9-135714735-C-CGG

Position:

• chr9-135714735-C-CGG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020822.3(KCNT1):​c.254+18_254+19dupGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,344,286 control chromosomes in the GnomAD database, including 36,993 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6258 hom., cov: 21)
  • Exomes 𝑓: 0.22 (30735 hom.)
• Consequence: KCNT1 NM_020822.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.114

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 -16 ACMG points.

• BP6: Variant 9-135714735-C-CGG is Benign according to our data. Variant chr9-135714735-C-CGG is described in ClinVar as [Benign]. Clinvar id is 261362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.254+18_254+19dupGG		intron_variant		ENST00000371757.7	NP_065873.2
KCNT1	NM_001272003.2	c.110+12370_110+12371dupGG		intron_variant			NP_001258932.1
KCNT1	XM_011518878.4	c.389+18_389+19dupGG		intron_variant			XP_011517180.1
KCNT1	XM_011518879.4	c.389+18_389+19dupGG		intron_variant			XP_011517181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.254+18_254+19dupGG		intron_variant		1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes AF: 0.277 AC: 41440 AN: 149590 Hom.: 6241 Cov.: 21

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.254

GnomAD3 exomes AF: 0.208 AC: 19562 AN: 94148 Hom.: 2213 AF XY: 0.213 AC XY: 11604 AN XY: 54490

Gnomad AFR exome AF: 0.354

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.215

Gnomad SAS exome AF: 0.280

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.219 AC: 261221 AN: 1194588 Hom.: 30735 Cov.: 30 AF XY: 0.219 AC XY: 128745 AN XY: 587644

Gnomad4 AFR exome AF: 0.392

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.217

GnomAD4 genome AF: 0.277 AC: 41504 AN: 149698 Hom.: 6258 Cov.: 21 AF XY: 0.274 AC XY: 20049 AN XY: 73042

Gnomad4 AFR AF: 0.408

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.255

Alfa AF: 0.250 Hom.: 491

Asia WGS AF: 0.248 AC: 802 AN: 3230

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 41. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, flagged submission	clinical testing	GeneDx	Jan 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2018	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141291153; hg19: chr9-138606581;