12-51779543-T-C

Variant names:

• chr12-51779543-T-C
• rs17126078
• NM_001330260.2:c.3820-1106T>C

Variant summary

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

The NM_001330260.2(SCN8A):​c.3820-1106T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,124 control chromosomes in the GnomAD database, including 1,451 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 0.12 (1451 hom., cov: 32)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.3820-1106T>C		intron_variant	Intron 20 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.3820-1106T>C		intron_variant	Intron 20 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.3819+5181T>C		intron_variant	Intron 20 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.3819+5181T>C		intron_variant	Intron 20 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.3820-1106T>C		intron_variant	Intron 20 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.3820-1106T>C		intron_variant	Intron 20 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.3853-1106T>C		intron_variant	Intron 19 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.3819+5181T>C		intron_variant	Intron 19 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18959 AN: 152006 Hom.: 1455 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0840

Gnomad OTH AF: 0.109

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

GnomAD4 genome AF: 0.125 AC: 18958 AN: 152124 Hom.: 1451 Cov.: 32 AF XY: 0.132 AC XY: 9818 AN XY: 74354

African (AFR) AF: 0.141 AC: 5840 AN: 41488

American (AMR) AF: 0.115 AC: 1751 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 494 AN: 3466

East Asian (EAS) AF: 0.365 AC: 1888 AN: 5176

South Asian (SAS) AF: 0.223 AC: 1076 AN: 4824

European-Finnish (FIN) AF: 0.178 AC: 1878 AN: 10564

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0840 AC: 5715 AN: 68004

Other (OTH) AF: 0.108 AC: 227 AN: 2110

Alfa AF: 0.0946 Hom.: 840

Bravo AF: 0.124

Asia WGS AF: 0.261 AC: 905 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.69
PhyloP100		-0.095
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: rs17126078; hg19: chr12-52173327;