rs303815

Variant names:

• chr12-51790487-T-C
• rs303815
• NM_001330260.2:c.4509T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-51790487-T-C
• chr12-51790487-T-A
• chr12-51790487-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001330260.2(SCN8A):​c.4509T>C​(p.Pro1503Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,605,698 control chromosomes in the GnomAD database, including 409,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (31602 hom., cov: 32)
  • Exomes 𝑓: 0.71 (377731 hom.)
• Consequence: SCN8A NM_001330260.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.204
• Publications: 29 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 12-51790487-T-C is Benign according to our data. Variant chr12-51790487-T-C is described in ClinVar as Benign. ClinVar VariationId is 130247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.204 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

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.4509T>C	p.Pro1503Pro	synonymous	Exon 25 of 27	NP_001317189.1	Q9UQD0-2
	SCN8A	NM_014191.4	MANE Plus Clinical	c.4509T>C	p.Pro1503Pro	synonymous	Exon 25 of 27	NP_055006.1	Q9UQD0-1
	SCN8A	NM_001177984.3		c.4386T>C	p.Pro1462Pro	synonymous	Exon 24 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.4509T>C	p.Pro1503Pro	synonymous	Exon 25 of 27	ENSP00000346534.4	Q9UQD0-1
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.4509T>C	p.Pro1503Pro	synonymous	Exon 25 of 27	ENSP00000487583.2	Q9UQD0-2
	SCN8A	ENST00000599343.5	TSL:5	c.4542T>C	p.Pro1514Pro	synonymous	Exon 24 of 26	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes AF: 0.619 AC: 93999 AN: 151974 Hom.: 31592 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.666

GnomAD2 exomes AF: 0.659 AC: 160565 AN: 243610 AF XY: 0.650

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.753

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.575

Gnomad FIN exome AF: 0.725

Gnomad NFE exome AF: 0.752

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.711 AC: 1033818 AN: 1453606 Hom.: 377731 Cov.: 32 AF XY: 0.702 AC XY: 507484 AN XY: 722938

African (AFR) AF: 0.336 AC: 11129 AN: 33156

American (AMR) AF: 0.751 AC: 32971 AN: 43932

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 17658 AN: 26032

East Asian (EAS) AF: 0.532 AC: 20866 AN: 39228

South Asian (SAS) AF: 0.367 AC: 31161 AN: 84852

European-Finnish (FIN) AF: 0.737 AC: 39321 AN: 53334

Middle Eastern (MID) AF: 0.620 AC: 3563 AN: 5744

European-Non Finnish (NFE) AF: 0.755 AC: 835694 AN: 1107254

Other (OTH) AF: 0.690 AC: 41455 AN: 60074

GnomAD4 genome AF: 0.618 AC: 94028 AN: 152092 Hom.: 31602 Cov.: 32 AF XY: 0.613 AC XY: 45614 AN XY: 74364

African (AFR) AF: 0.351 AC: 14549 AN: 41472

American (AMR) AF: 0.726 AC: 11102 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2281 AN: 3470

East Asian (EAS) AF: 0.577 AC: 2988 AN: 5176

South Asian (SAS) AF: 0.365 AC: 1757 AN: 4814

European-Finnish (FIN) AF: 0.710 AC: 7503 AN: 10574

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.758 AC: 51529 AN: 67970

Other (OTH) AF: 0.661 AC: 1397 AN: 2112

Alfa AF: 0.702 Hom.: 138157

Bravo AF: 0.615

Asia WGS AF: 0.446 AC: 1548 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Cognitive impairment with or without cerebellar ataxia (1)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Developmental and epileptic encephalopathy, 13 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Myoclonus, familial, 2 (1)
-	-	1	Seizures, benign familial infantile, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.73
PhyloP100		-0.20
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: rs303815; hg19: chr12-52184271; COSMIC: COSV61988449; COSMIC: COSV61988449;