12-51699614-C-T

Variant names:

• chr12-51699614-C-T
• rs200307006
• NM_001330260.2:c.751C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001330260.2(SCN8A):​c.751C>T​(p.Leu251Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000177 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L251L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SCN8A NM_001330260.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.17
• 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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 12-51699614-C-T is Benign according to our data. Variant chr12-51699614-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 207095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 31 AD gene.

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.751C>T	p.Leu251Leu	synonymous	Exon 7 of 27	NP_001317189.1	Q9UQD0-2
	SCN8A	NM_014191.4	MANE Plus Clinical	c.751C>T	p.Leu251Leu	synonymous	Exon 7 of 27	NP_055006.1	Q9UQD0-1
	SCN8A	NM_001177984.3		c.751C>T	p.Leu251Leu	synonymous	Exon 7 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.751C>T	p.Leu251Leu	synonymous	Exon 7 of 27	ENSP00000346534.4	Q9UQD0-1
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.751C>T	p.Leu251Leu	synonymous	Exon 7 of 27	ENSP00000487583.2	Q9UQD0-2
	SCN8A	ENST00000599343.5	TSL:5	c.751C>T	p.Leu251Leu	synonymous	Exon 6 of 26	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00808

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000313 AC: 78 AN: 249330 AF XY: 0.000333

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000174 AC: 255 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.000186 AC XY: 135 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00673 AC: 176 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111986

Other (OTH) AF: 0.000629 AC: 38 AN: 60394

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152092 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 28 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000449 Hom.: 1

Bravo AF: 0.000170

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.80
PhyloP100		6.2

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: rs200307006; hg19: chr12-52093398;