chr12-51745885-C-CT

Position:

• chr12-51745885-C-CT

Variant summary

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

The NM_014191.4(SCN8A):​c.1999-5dup 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 0.0709 in 1,061,912 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.082 (2 hom.)
• Consequence: SCN8A NM_014191.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 12-51745885-C-CT is Benign according to our data. Variant chr12-51745885-C-CT is described in ClinVar as [Benign]. Clinvar id is 1294100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 329 AN: 142782 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00160

Gnomad ASJ AF: 0.000907

Gnomad EAS AF: 0.000803

Gnomad SAS AF: 0.00469

Gnomad FIN AF: 0.00352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.000516

GnomAD3 exomes AF: 0.0969 AC: 7760 AN: 80108 Hom.: 0 AF XY: 0.0980 AC XY: 4189 AN XY: 42762

Gnomad AFR exome AF: 0.0967

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0853

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.0815 AC: 74942 AN: 919090 Hom.: 2 Cov.: 0 AF XY: 0.0813 AC XY: 37293 AN XY: 458990

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.0805

Gnomad4 ASJ exome AF: 0.0866

Gnomad4 EAS exome AF: 0.0784

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.0715

Gnomad4 NFE exome AF: 0.0808

Gnomad4 OTH exome AF: 0.0821

GnomAD4 genome AF: 0.00233 AC: 333 AN: 142822 Hom.: 0 Cov.: 31 AF XY: 0.00245 AC XY: 170 AN XY: 69418

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00160

Gnomad4 ASJ AF: 0.000907

Gnomad4 EAS AF: 0.000805

Gnomad4 SAS AF: 0.00471

Gnomad4 FIN AF: 0.00352

Gnomad4 NFE AF: 0.00292

Gnomad4 OTH AF: 0.000512

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 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;