rs375785915

chr12-51780642-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014191.4(SCN8A):c.3820-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 1,448,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SCN8A NM_014191.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006663
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.753

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-51780642-T-C is Benign according to our data. Variant chr12-51780642-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 461341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51780642-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000189 (28/147980) while in subpopulation AFR AF= 0.000651 (26/39924). AF 95% confidence interval is 0.000456. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.3820-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000627620.5
SCN8A	NM_014191.4	c.3820-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000354534.11
SCN8A	NM_001177984.3	c.3820-5900T>C		intron_variant
SCN8A	NM_001369788.1	c.3820-5900T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.3820-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.3820-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.000189 AC: 28 AN: 147868 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 9 AN: 133124 Hom.: 0 AF XY: 0.0000274 AC XY: 2 AN XY: 73050

Gnomad AFR exome AF: 0.000654

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000309

GnomAD4 exome AF: 0.0000215 AC: 28 AN: 1300096 Hom.: 0 Cov.: 21 AF XY: 0.0000171 AC XY: 11 AN XY: 643314

Gnomad4 AFR exome AF: 0.000543

Gnomad4 AMR exome AF: 0.000438

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000194

Gnomad4 OTH exome AF: 0.0000562

GnomAD4 genome AF: 0.000189 AC: 28 AN: 147980 Hom.: 0 Cov.: 22 AF XY: 0.000153 AC XY: 11 AN XY: 72092

Gnomad4 AFR AF: 0.000651

Gnomad4 AMR AF: 0.000136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000932 Hom.: 0

Bravo AF: 0.000280

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

SCN8A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.5
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.0
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: rs375785915; hg19: chr12-52174426;