rs1586098

Variant names:

• chr12-51653522-A-G
• rs1586098
• NM_001330260.2:c.-54-9242A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330260.2(SCN8A):​c.-54-9242A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 152,050 control chromosomes in the GnomAD database, including 42,950 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (42950 hom., cov: 32)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0830
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cognitive impairment with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile convulsions and choreoathetosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonus, familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.-54-9242A>G		intron_variant	Intron 1 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.-54-9242A>G		intron_variant	Intron 1 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.-54-9242A>G		intron_variant	Intron 1 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.-54-9242A>G		intron_variant	Intron 1 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.-54-9242A>G		intron_variant	Intron 1 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.-54-9242A>G		intron_variant	Intron 1 of 26	5	NM_001330260.2	ENSP00000487583.2

Frequencies

GnomAD3 genomes AF: 0.731 AC: 110988 AN: 151932 Hom.: 42937 Cov.: 32

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.905

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.752

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.730 AC: 111043 AN: 152050 Hom.: 42950 Cov.: 32 AF XY: 0.733 AC XY: 54500 AN XY: 74342

African (AFR) AF: 0.465 AC: 19246 AN: 41408

American (AMR) AF: 0.812 AC: 12418 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2506 AN: 3470

East Asian (EAS) AF: 0.858 AC: 4439 AN: 5172

South Asian (SAS) AF: 0.594 AC: 2856 AN: 4812

European-Finnish (FIN) AF: 0.905 AC: 9589 AN: 10592

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.844 AC: 57404 AN: 67984

Other (OTH) AF: 0.748 AC: 1579 AN: 2112

Alfa AF: 0.777 Hom.: 6162

Bravo AF: 0.719

Asia WGS AF: 0.682 AC: 2367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.0
DANN	Benign	0.87
PhyloP100		0.083
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1586098; hg19: chr12-52047306;