rs2099715

Variant names:

• chr12-51800099-G-A
• rs2099715
• NM_001330260.2:c.4795+5458G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51800099-G-A
• chr12-51800099-G-T

Variant summary

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

The NM_001330260.2(SCN8A):​c.4795+5458G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,252 control chromosomes in the GnomAD database, including 1,135 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 0.11 (1135 hom., cov: 33)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.226
• Publications: 2 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=-0.63).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4795+5458G>A		intron_variant	Intron 26 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4795+5458G>A		intron_variant	Intron 26 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4672+5458G>A		intron_variant	Intron 25 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.4672+5458G>A		intron_variant	Intron 25 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4795+5458G>A		intron_variant	Intron 26 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4795+5458G>A		intron_variant	Intron 26 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4828+5458G>A		intron_variant	Intron 25 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4672+5458G>A		intron_variant	Intron 24 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16232 AN: 152134 Hom.: 1137 Cov.: 33

Gnomad AFR AF: 0.0801

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0955

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

GnomAD4 genome AF: 0.107 AC: 16230 AN: 152252 Hom.: 1135 Cov.: 33 AF XY: 0.115 AC XY: 8571 AN XY: 74436

African (AFR) AF: 0.0801 AC: 3327 AN: 41546

American (AMR) AF: 0.106 AC: 1615 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3470

East Asian (EAS) AF: 0.364 AC: 1881 AN: 5170

South Asian (SAS) AF: 0.223 AC: 1077 AN: 4828

European-Finnish (FIN) AF: 0.179 AC: 1891 AN: 10592

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0835 AC: 5681 AN: 68030

Other (OTH) AF: 0.0945 AC: 200 AN: 2116

Alfa AF: 0.0871 Hom.: 605

Bravo AF: 0.102

Asia WGS AF: 0.257 AC: 893 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		0.23
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: rs2099715; hg19: chr12-52193883;