12-51745885-CTTT-CTT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_014191.4(SCN8A):c.1999-5del 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 0.148 in 957,358 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 31)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: SCN8A NM_014191.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.316

Genes affected

SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 12-51745885-CT-C is Benign according to our data. Variant chr12-51745885-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212134.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr12-51745885-CT-C is described in Lovd as [Benign]. Variant chr12-51745885-CT-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.1999-5del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000627620.5
SCN8A	NM_014191.4	c.1999-5del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000354534.11
SCN8A	NM_001177984.3	c.1999-5del		splice_polypyrimidine_tract_variant, intron_variant
SCN8A	NM_001369788.1	c.1999-5del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.1999-5del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.1999-5del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 496 AN: 142350 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00286

Gnomad ASJ AF: 0.00182

Gnomad EAS AF: 0.000402

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00465

GnomAD3 exomes AF: 0.244 AC: 19513 AN: 80108 Hom.: 0 AF XY: 0.258 AC XY: 11020 AN XY: 42762

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.290

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.241

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.174 AC: 141659 AN: 814970 Hom.: 0 Cov.: 0 AF XY: 0.175 AC XY: 71493 AN XY: 407610

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.181

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.184

GnomAD4 genome AF: 0.00350 AC: 498 AN: 142388 Hom.: 1 Cov.: 31 AF XY: 0.00377 AC XY: 261 AN XY: 69154

Gnomad4 AFR AF: 0.00179

Gnomad4 AMR AF: 0.00286

Gnomad4 ASJ AF: 0.00182

Gnomad4 EAS AF: 0.000403

Gnomad4 SAS AF: 0.000450

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.00376

Gnomad4 OTH AF: 0.00461

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 17, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2018

This alteration is classified as likely 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. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs769940455; hg19: chr12-52139669;