rs117217073

chr12-51769039-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_014191.4(SCN8A):c.3076C>T(p.Arg1026Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,932 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1026H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 32)
  • Exomes 𝑓: 0.013 (167 hom.)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.53

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN8A
• BP4: Computational evidence support a benign effect (MetaRNN=0.006647438).
• BP6: Variant 12-51769039-C-T is Benign according to our data. Variant chr12-51769039-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130244.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}. Variant chr12-51769039-C-T is described in Lovd as [Likely_benign]. Variant chr12-51769039-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1629/152276) while in subpopulation NFE AF= 0.0146 (991/68024). AF 95% confidence interval is 0.0138. There are 16 homozygotes in gnomad4. There are 879 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1630 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.3076C>T	p.Arg1026Cys	missense_variant	17/27	ENST00000627620.5
SCN8A	NM_014191.4	c.3076C>T	p.Arg1026Cys	missense_variant	17/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.3076C>T	p.Arg1026Cys	missense_variant	17/26
SCN8A	NM_001369788.1	c.3076C>T	p.Arg1026Cys	missense_variant	17/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.3076C>T	p.Arg1026Cys	missense_variant	17/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.3076C>T	p.Arg1026Cys	missense_variant	17/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1630 AN: 152158 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0351

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.0117 AC: 2916 AN: 249052 Hom.: 33 AF XY: 0.0119 AC XY: 1604 AN XY: 135122

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00415

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.00975

GnomAD4 exome AF: 0.0127 AC: 18504 AN: 1461656 Hom.: 167 Cov.: 31 AF XY: 0.0127 AC XY: 9228 AN XY: 727102

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00470

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0107 AC: 1629 AN: 152276 Hom.: 16 Cov.: 32 AF XY: 0.0118 AC XY: 879 AN XY: 74454

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0351

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.0133 Hom.: 23

Bravo AF: 0.00829

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00193 AC: 8

ESP6500EA AF: 0.0155 AC: 131

ExAC AF: 0.0117 AC: 1419

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0138

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 08, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN8A: PP2, BS1, BS2 -

Developmental and epileptic encephalopathy, 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics

Feb 14, 2020

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 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. -

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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;.;D;D
MetaRNN	Benign	0.0066	T;T;T;T;T
MetaSVM	Uncertain	0.072	D
MutationAssessor	Benign	1.8	L;L;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.2	D;D;D;.;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.030	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.33
MPC		1.4
ClinPred		0.027	T
GERP RS		4.5
Varity_R		0.49
gMVP		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: rs117217073; hg19: chr12-52162823;