rs303810

chr12-51769464-A-Gchr12-51769464-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014191.4(SCN8A):c.3372+129A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 648,914 control chromosomes in the GnomAD database, including 214,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.74 (43794 hom., cov: 30)
  • Exomes 𝑓: 0.82 (170647 hom.)
• Consequence: SCN8A NM_014191.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.111

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-51769464-A-G is Benign according to our data. Variant chr12-51769464-A-G is described in ClinVar as [Benign]. Clinvar id is 669362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.3372+129A>G		intron_variant		ENST00000627620.5
SCN8A	NM_014191.4	c.3372+129A>G		intron_variant		ENST00000354534.11
SCN8A	NM_001177984.3	c.3372+129A>G		intron_variant
SCN8A	NM_001369788.1	c.3372+129A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.3372+129A>G		intron_variant		1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.3372+129A>G		intron_variant		5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111874 AN: 151884 Hom.: 43795 Cov.: 30

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.903

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.772

GnomAD4 exome AF: 0.822 AC: 408302 AN: 496912 Hom.: 170647 AF XY: 0.811 AC XY: 210543 AN XY: 259678

Gnomad4 AFR exome AF: 0.448

Gnomad4 AMR exome AF: 0.859

Gnomad4 ASJ exome AF: 0.813

Gnomad4 EAS exome AF: 0.916

Gnomad4 SAS exome AF: 0.588

Gnomad4 FIN exome AF: 0.902

Gnomad4 NFE exome AF: 0.854

Gnomad4 OTH exome AF: 0.807

GnomAD4 genome AF: 0.736 AC: 111893 AN: 152002 Hom.: 43794 Cov.: 30 AF XY: 0.738 AC XY: 54877 AN XY: 74330

Gnomad4 AFR AF: 0.448

Gnomad4 AMR AF: 0.834

Gnomad4 ASJ AF: 0.802

Gnomad4 EAS AF: 0.899

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.903

Gnomad4 NFE AF: 0.855

Gnomad4 OTH AF: 0.767

Alfa AF: 0.796 Hom.: 8467

Bravo AF: 0.725

Asia WGS AF: 0.683 AC: 2373 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	4.9
Dann	Benign	0.70

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: rs303810; hg19: chr12-52163248;