12-51706589-C-G

Variant names:

• chr12-51706589-C-G
• rs376749872
• NM_001330260.2:c.1509C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_014191.4(SCN8A):​c.1509C>G​(p.Leu503Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L503L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN8A NM_014191.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.813
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=-0.813 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014191.4. 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.1509C>G	p.Leu503Leu	synonymous	Exon 11 of 27	NP_001317189.1
	SCN8A	NM_014191.4	MANE Plus Clinical	c.1509C>G	p.Leu503Leu	synonymous	Exon 11 of 27	NP_055006.1
	SCN8A	NM_001177984.3		c.1509C>G	p.Leu503Leu	synonymous	Exon 11 of 26	NP_001171455.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.1509C>G	p.Leu503Leu	synonymous	Exon 11 of 27	ENSP00000346534.4
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.1509C>G	p.Leu503Leu	synonymous	Exon 11 of 27	ENSP00000487583.2
	SCN8A	ENST00000599343.5	TSL:5	c.1509C>G	p.Leu503Leu	synonymous	Exon 10 of 26	ENSP00000476447.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456462 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724002

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 43972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109340

Other (OTH) AF: 0.00 AC: 0 AN: 60188

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	4.5
DANN	Benign	0.74
PhyloP100		-0.81

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: rs376749872; hg19: chr12-52100373;