12-51774913-G-A

Variant names:

• chr12-51774913-G-A
• rs12581041
• NM_001330260.2:c.3819+551G>A

Variant summary

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

The NM_001330260.2(SCN8A):​c.3819+551G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,112 control chromosomes in the GnomAD database, including 1,176 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 (1176 hom., cov: 32)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0630
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 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.3819+551G>A		intron	N/A	NP_001317189.1
	SCN8A	NM_014191.4	MANE Plus Clinical	c.3819+551G>A		intron	N/A	NP_055006.1
	SCN8A	NM_001177984.3		c.3819+551G>A		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.3819+551G>A		intron	N/A	ENSP00000346534.4
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.3819+551G>A		intron	N/A	ENSP00000487583.2
	SCN8A	ENST00000599343.5	TSL:5	c.3852+551G>A		intron	N/A	ENSP00000476447.3

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16482 AN: 151992 Hom.: 1179 Cov.: 32

Gnomad AFR AF: 0.0887

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0824

Gnomad OTH AF: 0.0957

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

GnomAD4 genome AF: 0.108 AC: 16476 AN: 152112 Hom.: 1176 Cov.: 32 AF XY: 0.117 AC XY: 8665 AN XY: 74356

African (AFR) AF: 0.0885 AC: 3674 AN: 41508

American (AMR) AF: 0.105 AC: 1609 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3472

East Asian (EAS) AF: 0.363 AC: 1875 AN: 5162

South Asian (SAS) AF: 0.223 AC: 1076 AN: 4820

European-Finnish (FIN) AF: 0.178 AC: 1881 AN: 10562

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

European-Non Finnish (NFE) AF: 0.0823 AC: 5599 AN: 67992

Other (OTH) AF: 0.0947 AC: 200 AN: 2112

Alfa AF: 0.0618 Hom.: 99

Bravo AF: 0.104

Asia WGS AF: 0.253 AC: 878 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.57
DANN	Benign	0.69
PhyloP100		-0.063
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: rs12581041; hg19: chr12-52168697;