rs303810

Variant names:

• chr12-51769464-A-G
• rs303810
• NM_001330260.2:c.3372+129A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-51769464-A-G
• chr12-51769464-A-T

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.3372+129A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 648,914 control chromosomes in the GnomAD database, including 214,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43794 hom., cov: 30)
  • Exomes 𝑓: 0.82 (170647 hom.)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.111
• Publications: 6 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 12-51769464-A-G is Benign according to our data. Variant chr12-51769464-A-G is described in ClinVar as Benign. ClinVar VariationId is 669362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.3372+129A>G		intron_variant	Intron 17 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.3372+129A>G		intron_variant	Intron 17 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.3372+129A>G		intron_variant	Intron 17 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.3372+129A>G		intron_variant	Intron 17 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.3372+129A>G		intron_variant	Intron 17 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.3372+129A>G		intron_variant	Intron 17 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.3405+129A>G		intron_variant	Intron 16 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.3372+129A>G		intron_variant	Intron 16 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111874 AN: 151884 Hom.: 43795 Cov.: 30

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.903

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.772

GnomAD4 exome AF: 0.822 AC: 408302 AN: 496912 Hom.: 170647 AF XY: 0.811 AC XY: 210543 AN XY: 259678

African (AFR) AF: 0.448 AC: 5960 AN: 13290

American (AMR) AF: 0.859 AC: 16120 AN: 18776

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 11366 AN: 13974

East Asian (EAS) AF: 0.916 AC: 28737 AN: 31386

South Asian (SAS) AF: 0.588 AC: 26542 AN: 45152

European-Finnish (FIN) AF: 0.902 AC: 29701 AN: 32930

Middle Eastern (MID) AF: 0.731 AC: 1512 AN: 2068

European-Non Finnish (NFE) AF: 0.854 AC: 266085 AN: 311734

Other (OTH) AF: 0.807 AC: 22279 AN: 27602

GnomAD4 genome AF: 0.736 AC: 111893 AN: 152002 Hom.: 43794 Cov.: 30 AF XY: 0.738 AC XY: 54877 AN XY: 74330

African (AFR) AF: 0.448 AC: 18539 AN: 41376

American (AMR) AF: 0.834 AC: 12747 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2784 AN: 3470

East Asian (EAS) AF: 0.899 AC: 4634 AN: 5152

South Asian (SAS) AF: 0.591 AC: 2842 AN: 4812

European-Finnish (FIN) AF: 0.903 AC: 9578 AN: 10604

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.855 AC: 58133 AN: 67984

Other (OTH) AF: 0.767 AC: 1620 AN: 2112

Alfa AF: 0.785 Hom.: 8535

Bravo AF: 0.725

Asia WGS AF: 0.683 AC: 2373 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 25. Only high quality variants are reported. -

not provided Benign:1

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.70
PhyloP100		0.11
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: rs303810; hg19: chr12-52163248;