rs770747359

Positions:

• chr12-51769859-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014191.4(SCN8A):​c.3373-9C>T 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 0.0000607 in 1,565,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: SCN8A NM_014191.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003172
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.612

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-51769859-C-T is Benign according to our data. Variant chr12-51769859-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 530519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51769859-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.3373-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.3373-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.3373-9C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_001171455.1
SCN8A	NM_001369788.1	c.3373-9C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.3373-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.3373-9C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000444 AC: 9 AN: 202830 Hom.: 0 AF XY: 0.0000463 AC XY: 5 AN XY: 108044

Gnomad AFR exome AF: 0.0000844

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000687

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000788

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000552 AC: 78 AN: 1413658 Hom.: 0 Cov.: 28 AF XY: 0.0000599 AC XY: 42 AN XY: 700894

Gnomad4 AFR exome AF: 0.000246

Gnomad4 AMR exome AF: 0.0000757

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000592

Gnomad4 OTH exome AF: 0.0000340

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74294

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000982

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

- -

SCN8A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0020
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: rs770747359; hg19: chr12-52163643;