rs372582842

Variant names:

• chr12-51765758-C-T
• rs372582842
• NM_001330260.2:c.2632C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_001330260.2(SCN8A):​c.2632C>T​(p.Leu878Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000302 in 1,613,870 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene SCN8A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: SCN8A NM_001330260.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.617
• 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, STRONG Submitted by: ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 13

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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

Specifications for SCN8A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-51765758-C-T is Benign according to our data. Variant chr12-51765758-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.617 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00162 (246/152160) while in subpopulation AFR AF = 0.00576 (239/41510). AF 95% confidence interval is 0.00516. There are 1 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330260.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	NM_001330260.2	MANE Select	c.2632C>T	p.Leu878Leu	synonymous	Exon 16 of 27	NP_001317189.1	Q9UQD0-2
	SCN8A	NM_014191.4	MANE Plus Clinical	c.2632C>T	p.Leu878Leu	synonymous	Exon 16 of 27	NP_055006.1	Q9UQD0-1
	SCN8A	NM_001177984.3		c.2632C>T	p.Leu878Leu	synonymous	Exon 16 of 26	NP_001171455.1	Q9UQD0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.2632C>T	p.Leu878Leu	synonymous	Exon 16 of 27	ENSP00000346534.4	Q9UQD0-1
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.2632C>T	p.Leu878Leu	synonymous	Exon 16 of 27	ENSP00000487583.2	Q9UQD0-2
	SCN8A	ENST00000599343.5	TSL:5	c.2665C>T	p.Leu889Leu	synonymous	Exon 15 of 26	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152044 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000428 AC: 107 AN: 249986 AF XY: 0.000369

Gnomad AFR exome AF: 0.00593

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1461710 Hom.: 1 Cov.: 32 AF XY: 0.000146 AC XY: 106 AN XY: 727126

African (AFR) AF: 0.00570 AC: 191 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111878

Other (OTH) AF: 0.000348 AC: 21 AN: 60384

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152160 Hom.: 1 Cov.: 31 AF XY: 0.00137 AC XY: 102 AN XY: 74382

African (AFR) AF: 0.00576 AC: 239 AN: 41510

American (AMR) AF: 0.000392 AC: 6 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000958 Hom.: 0

Bravo AF: 0.00187

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.6
DANN	Benign	0.77
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism

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: rs372582842; hg19: chr12-52159542;