rs115623439

chr12-51786721-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014191.4(SCN8A):c.4122T>A(p.Thr1374=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,613,956 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (11 hom.)
• Consequence: SCN8A NM_014191.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.37

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 12-51786721-T-A is Benign according to our data. Variant chr12-51786721-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 130246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51786721-T-A is described in Lovd as [Benign]. Variant chr12-51786721-T-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00489 (744/152300) while in subpopulation AFR AF= 0.0164 (682/41558). AF 95% confidence interval is 0.0154. There are 1 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 741 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4122T>A	p.Thr1374=	synonymous_variant	22/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4122T>A	p.Thr1374=	synonymous_variant	22/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.3999T>A	p.Thr1333=	synonymous_variant	21/26
SCN8A	NM_001369788.1	c.3999T>A	p.Thr1333=	synonymous_variant	21/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.4122T>A	p.Thr1374=	synonymous_variant	22/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.4122T>A	p.Thr1374=	synonymous_variant	22/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 741 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00125 AC: 312 AN: 249010 Hom.: 0 AF XY: 0.000992 AC XY: 134 AN XY: 135070

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000928

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000699 AC: 1021 AN: 1461656 Hom.: 11 Cov.: 32 AF XY: 0.000626 AC XY: 455 AN XY: 727102

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00489 AC: 744 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00459 AC XY: 342 AN XY: 74468

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.00548

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2013	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2018	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2016

This alteration is classified as 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. -

Cognitive impairment with or without cerebellar ataxia;C3281191:Developmental and epileptic encephalopathy, 13;C4310728:Seizures, benign familial infantile, 5;C5193056:Myoclonus, familial, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	2.0
Dann	Benign	0.63

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: rs115623439; hg19: chr12-52180505;