rs376749872

Positions:

• chr12-51706589-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001330260.2(SCN8A):​c.1509C>A​(p.Leu503Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,608,736 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 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: SCN8A NM_001330260.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.813

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]

SCN8A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 12-51706589-C-A is Benign according to our data. Variant chr12-51706589-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 207097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.813 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000536 (78/1456462) while in subpopulation MID AF= 0.000521 (3/5762). AF 95% confidence interval is 0.000338. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1509C>A	p.Leu503Leu	synonymous_variant	11/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1509C>A	p.Leu503Leu	synonymous_variant	11/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1509C>A	p.Leu503Leu	synonymous_variant	11/26		NP_001171455.1
SCN8A	NM_001369788.1	c.1509C>A	p.Leu503Leu	synonymous_variant	11/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1509C>A	p.Leu503Leu	synonymous_variant	11/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1509C>A	p.Leu503Leu	synonymous_variant	11/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.1509C>A	p.Leu503Leu	synonymous_variant	10/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1509C>A	p.Leu503Leu	synonymous_variant	10/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000113 AC: 27 AN: 238930 Hom.: 0 AF XY: 0.0000927 AC XY: 12 AN XY: 129384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000597

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000580

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000465

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000536 AC: 78 AN: 1456462 Hom.: 0 Cov.: 31 AF XY: 0.0000511 AC XY: 37 AN XY: 724002

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000500

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000361

Gnomad4 OTH exome AF: 0.0000831

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74474

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2015

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2016

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

SCN8A: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	4.0
DANN	Benign	0.75

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: rs376749872; hg19: chr12-52100373;