rs187327463

Positions:

• chr12-51780651-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001330260.2(SCN8A):​c.3822C>T​(p.Val1274Val) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00205 in 1,254,198 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 23)
  • Exomes 𝑓: 0.0021 (0 hom.)
• Consequence: SCN8A NM_001330260.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.05

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 12-51780651-C-T is Benign according to our data. Variant chr12-51780651-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51780651-C-T is described in Lovd as [Benign]. Variant chr12-51780651-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00136 (168/123406) while in subpopulation NFE AF= 0.00191 (116/60846). AF 95% confidence interval is 0.00162. There are 2 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.3822C>T	p.Val1274Val	splice_region_variant, synonymous_variant	21/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.3822C>T	p.Val1274Val	splice_region_variant, synonymous_variant	21/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.3820-5891C>T		intron_variant			NP_001171455.1
SCN8A	NM_001369788.1	c.3820-5891C>T		intron_variant			NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.3822C>T	p.Val1274Val	splice_region_variant, synonymous_variant	21/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.3822C>T	p.Val1274Val	splice_region_variant, synonymous_variant	21/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.3855C>T	p.Val1285Val	splice_region_variant, synonymous_variant	20/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.3820-5891C>T		intron_variant		1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 168 AN: 123330 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000184

Gnomad AMI AF: 0.00124

Gnomad AMR AF: 0.000660

Gnomad ASJ AF: 0.00856

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000590

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00121

GnomAD3 exomes AF: 0.00180 AC: 251 AN: 139640 Hom.: 0 AF XY: 0.00186 AC XY: 144 AN XY: 77336

Gnomad AFR exome AF: 0.000406

Gnomad AMR exome AF: 0.000577

Gnomad ASJ exome AF: 0.00681

Gnomad EAS exome AF: 0.000648

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000766

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.00212 AC: 2402 AN: 1130792 Hom.: 0 Cov.: 28 AF XY: 0.00211 AC XY: 1174 AN XY: 556316

Gnomad4 AFR exome AF: 0.000319

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.000808

Gnomad4 NFE exome AF: 0.00218

Gnomad4 OTH exome AF: 0.00261

GnomAD4 genome AF: 0.00136 AC: 168 AN: 123406 Hom.: 2 Cov.: 23 AF XY: 0.00120 AC XY: 70 AN XY: 58116

Gnomad4 AFR AF: 0.000184

Gnomad4 AMR AF: 0.000659

Gnomad4 ASJ AF: 0.00856

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000589

Gnomad4 FIN AF: 0.00111

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.00120

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00134

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SCN8A: BP4, BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2014	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 12, 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Developmental and epileptic encephalopathy, 13 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs187327463; hg19: chr12-52174435;