rs757968008

Positions:

• chr9-135786170-CGCCCTGCCCT-C
• chr9-135786170-CGCCCTGCCCT-CGCCCT
• chr9-135786170-CGCCCTGCCCT-CGCCCTGCCCTGCCCT
• chr9-135786170-CGCCCTGCCCT-CGCCCTGCCCTGCCCTGCCCT
• chr9-135786170-CGCCCTGCCCT-CGCCCTGCCCTGCCCTGCCCTGCCCT
• chr9-135786170-CGCCCTGCCCT-CGCCCTGCCCTGCCCTGCCCTGCCCTGCCCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.3178-12_3178-3del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,548,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: KCNT1 NM_020822.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.02

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 9-135786170-CGCCCTGCCCT-C is Benign according to our data. Variant chr9-135786170-CGCCCTGCCCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 420320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000637 (96/150636) while in subpopulation AFR AF= 0.00189 (77/40750). AF 95% confidence interval is 0.00155. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.3178-12_3178-3del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.3178-12_3178-3del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 96 AN: 150522 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000592

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000213 AC: 42 AN: 197052 Hom.: 0 AF XY: 0.000228 AC XY: 25 AN XY: 109482

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.000220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000385

Gnomad FIN exome AF: 0.0000538

Gnomad NFE exome AF: 0.000218

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000136 AC: 190 AN: 1397610 Hom.: 0 AF XY: 0.000139 AC XY: 97 AN XY: 696448

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000732

Gnomad4 FIN exome AF: 0.0000396

Gnomad4 NFE exome AF: 0.0000927

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.000637 AC: 96 AN: 150636 Hom.: 0 Cov.: 0 AF XY: 0.000720 AC XY: 53 AN XY: 73582

Gnomad4 AFR AF: 0.00189

Gnomad4 AMR AF: 0.000592

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.000479

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 29, 2024

Variant summary: KCNT1 c.3178-12_3178-3del10 alters non-conserved nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 197052 control chromosomes. To our knowledge, no occurrence of c.3178-12_3178-3del10 in individuals affected with Developmental And Epileptic Encephalopathy, 14 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 420320). Based on the evidence outlined above, the variant was classified as Likely Benign. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2023

See Variant Classification Assertion Criteria. -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs757968008; hg19: chr9-138678016;