12-51788761-A-G

Variant names:

• chr12-51788761-A-G
• rs9943809
• NM_001330260.2:c.4281+13A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330260.2(SCN8A):​c.4281+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,603,488 control chromosomes in the GnomAD database, including 12,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (1020 hom., cov: 31)
  • Exomes 𝑓: 0.10 (11265 hom.)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.432
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-51788761-A-G is Benign according to our data. Variant chr12-51788761-A-G is described in ClinVar as Benign. ClinVar VariationId is 139073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.4281+13A>G		intron_variant	Intron 23 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4281+13A>G		intron_variant	Intron 23 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4158+13A>G		intron_variant	Intron 22 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.4158+13A>G		intron_variant	Intron 22 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4281+13A>G		intron_variant	Intron 23 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4281+13A>G		intron_variant	Intron 23 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4314+13A>G		intron_variant	Intron 22 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4158+13A>G		intron_variant	Intron 21 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.0902 AC: 13712 AN: 151976 Hom.: 1023 Cov.: 31

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.0832

GnomAD2 exomes AF: 0.133 AC: 32426 AN: 244588 AF XY: 0.135

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.356

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.0846

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.103 AC: 150049 AN: 1451394 Hom.: 11265 Cov.: 29 AF XY: 0.106 AC XY: 76578 AN XY: 721496

African (AFR) AF: 0.0203 AC: 677 AN: 33370

American (AMR) AF: 0.135 AC: 5973 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3376 AN: 25862

East Asian (EAS) AF: 0.426 AC: 16654 AN: 39052

South Asian (SAS) AF: 0.207 AC: 17340 AN: 83744

European-Finnish (FIN) AF: 0.158 AC: 8351 AN: 52904

Middle Eastern (MID) AF: 0.0746 AC: 429 AN: 5750

European-Non Finnish (NFE) AF: 0.0822 AC: 91006 AN: 1106574

Other (OTH) AF: 0.104 AC: 6243 AN: 59968

GnomAD4 genome AF: 0.0901 AC: 13701 AN: 152094 Hom.: 1020 Cov.: 31 AF XY: 0.0988 AC XY: 7345 AN XY: 74340

African (AFR) AF: 0.0229 AC: 951 AN: 41516

American (AMR) AF: 0.0964 AC: 1474 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3472

East Asian (EAS) AF: 0.364 AC: 1878 AN: 5156

South Asian (SAS) AF: 0.222 AC: 1062 AN: 4790

European-Finnish (FIN) AF: 0.182 AC: 1929 AN: 10576

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0836 AC: 5680 AN: 67980

Other (OTH) AF: 0.0823 AC: 174 AN: 2114

Alfa AF: 0.0914 Hom.: 468

Bravo AF: 0.0817

Asia WGS AF: 0.251 AC: 871 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.49
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs9943809; hg19: chr12-52182545; COSMIC: COSV61982179; COSMIC: COSV61982179;