rs201018451

Positions:

• chr12-51706504-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014191.4(SCN8A):​c.1424G>A​(p.Arg475Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000679 in 1,605,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R475W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.08

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN8A
• BP4: Computational evidence support a benign effect (MetaRNN=0.033465236).
• BP6: Variant 12-51706504-G-A is Benign according to our data. Variant chr12-51706504-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 167654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000289 (44/152270) while in subpopulation AFR AF= 0.000891 (37/41548). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.1424G>A	p.Arg475Gln	missense_variant	11/27	ENST00000627620.5
SCN8A	NM_014191.4	c.1424G>A	p.Arg475Gln	missense_variant	11/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.1424G>A	p.Arg475Gln	missense_variant	11/26
SCN8A	NM_001369788.1	c.1424G>A	p.Arg475Gln	missense_variant	11/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.1424G>A	p.Arg475Gln	missense_variant	11/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.1424G>A	p.Arg475Gln	missense_variant	11/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.0000387 AC: 9 AN: 232638 Hom.: 0 AF XY: 0.0000476 AC XY: 6 AN XY: 125968

Gnomad AFR exome AF: 0.000501

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000447 AC: 65 AN: 1452752 Hom.: 0 Cov.: 31 AF XY: 0.0000443 AC XY: 32 AN XY: 721708

Gnomad4 AFR exome AF: 0.000872

Gnomad4 AMR exome AF: 0.0000461

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000271

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74442

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.000825 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 12, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2019

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

Invitae

Nov 28, 2023

- -

SCN8A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2019

This variant is associated with the following publications: (PMID: 33083721) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T;T;.;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.033	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.072	D
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.35	T
Polyphen		0.0010	.;B;.;.;B;.;.
Vest4		0.12, 0.11, 0.12, 0.097
MVP		0.75
MPC		1.1
ClinPred		0.035	T
GERP RS		4.4
Varity_R		0.065
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201018451; hg19: chr12-52100288;