rs10506302

Variant names:

• chr12-51675683-C-T
• rs10506302
• NM_001330260.2:c.277-8491C>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.277-8491C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0583 in 152,130 control chromosomes in the GnomAD database, including 378 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 0.058 (378 hom., cov: 32)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.277-8491C>T		intron_variant	Intron 2 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.277-8491C>T		intron_variant	Intron 2 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.277-8491C>T		intron_variant	Intron 2 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.277-8491C>T		intron_variant	Intron 2 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.277-8491C>T		intron_variant	Intron 2 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.277-8491C>T		intron_variant	Intron 2 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.277-8491C>T		intron_variant	Intron 1 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.277-8491C>T		intron_variant	Intron 1 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8839 AN: 152010 Hom.: 371 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0499

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0938

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0609

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

GnomAD4 genome AF: 0.0583 AC: 8873 AN: 152130 Hom.: 378 Cov.: 32 AF XY: 0.0582 AC XY: 4327 AN XY: 74390

African (AFR) AF: 0.106 AC: 4415 AN: 41468

American (AMR) AF: 0.0502 AC: 767 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3472

East Asian (EAS) AF: 0.134 AC: 693 AN: 5170

South Asian (SAS) AF: 0.0939 AC: 452 AN: 4814

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10600

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1926 AN: 68004

Other (OTH) AF: 0.0674 AC: 142 AN: 2108

Alfa AF: 0.0400 Hom.: 218

Bravo AF: 0.0625

Asia WGS AF: 0.159 AC: 553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.28
DANN	Benign	0.74
PhyloP100		-1.5
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: rs10506302; hg19: chr12-52069467;