12-51674212-A-G

Variant names:

• chr12-51674212-A-G
• rs3782478
• NM_001330260.2:c.277-9962A>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.277-9962A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 152,148 control chromosomes in the GnomAD database, including 8,150 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 0.29 (8150 hom., cov: 32)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.345
• Publications: 3 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=-0.51).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330260.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	NM_001330260.2	MANE Select	c.277-9962A>G		intron	N/A	NP_001317189.1
	SCN8A	NM_014191.4	MANE Plus Clinical	c.277-9962A>G		intron	N/A	NP_055006.1
	SCN8A	NM_001177984.3		c.277-9962A>G		intron	N/A	NP_001171455.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.277-9962A>G		intron	N/A	ENSP00000346534.4
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.277-9962A>G		intron	N/A	ENSP00000487583.2
	SCN8A	ENST00000599343.5	TSL:5	c.277-9962A>G		intron	N/A	ENSP00000476447.3

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44104 AN: 152030 Hom.: 8152 Cov.: 32

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.0459

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.290 AC: 44102 AN: 152148 Hom.: 8150 Cov.: 32 AF XY: 0.288 AC XY: 21401 AN XY: 74370

African (AFR) AF: 0.0922 AC: 3828 AN: 41538

American (AMR) AF: 0.290 AC: 4430 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1178 AN: 3468

East Asian (EAS) AF: 0.0458 AC: 237 AN: 5176

South Asian (SAS) AF: 0.189 AC: 914 AN: 4824

European-Finnish (FIN) AF: 0.381 AC: 4020 AN: 10564

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28496 AN: 67974

Other (OTH) AF: 0.316 AC: 666 AN: 2110

Alfa AF: 0.370 Hom.: 21420

Bravo AF: 0.277

Asia WGS AF: 0.114 AC: 398 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.0
DANN	Benign	0.90
PhyloP100		-0.34
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: rs3782478; hg19: chr12-52067996;