NM_001330260.2:c.4228-427A>G

Variant names:

• chr12-51788268-A-G
• rs167337
• NM_001330260.2:c.4228-427A>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.4228-427A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.858 in 144,990 control chromosomes in the GnomAD database, including 53,565 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 0.86 (53565 hom., cov: 21)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4228-427A>G		intron_variant	Intron 22 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4228-427A>G		intron_variant	Intron 22 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4105-427A>G		intron_variant	Intron 21 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.4105-427A>G		intron_variant	Intron 21 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4228-427A>G		intron_variant	Intron 22 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4228-427A>G		intron_variant	Intron 22 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4261-427A>G		intron_variant	Intron 21 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4105-427A>G		intron_variant	Intron 20 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.858 AC: 124264 AN: 144876 Hom.: 53507 Cov.: 21

Gnomad AFR AF: 0.812

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.902

Gnomad ASJ AF: 0.830

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.901

Gnomad MID AF: 0.811

Gnomad NFE AF: 0.871

Gnomad OTH AF: 0.875

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

GnomAD4 genome AF: 0.858 AC: 124380 AN: 144990 Hom.: 53565 Cov.: 21 AF XY: 0.857 AC XY: 59958 AN XY: 69934

African (AFR) AF: 0.813 AC: 31401 AN: 38634

American (AMR) AF: 0.903 AC: 12957 AN: 14354

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 2875 AN: 3462

East Asian (EAS) AF: 0.976 AC: 4716 AN: 4832

South Asian (SAS) AF: 0.699 AC: 3180 AN: 4550

European-Finnish (FIN) AF: 0.901 AC: 7756 AN: 8610

Middle Eastern (MID) AF: 0.813 AC: 226 AN: 278

European-Non Finnish (NFE) AF: 0.871 AC: 58625 AN: 67324

Other (OTH) AF: 0.876 AC: 1787 AN: 2040

Alfa AF: 0.872 Hom.: 9818

Bravo AF: 0.864

Asia WGS AF: 0.859 AC: 2983 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.4
DANN	Benign	0.47
PhyloP100		-0.15
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: rs167337; hg19: chr12-52182052;