rs4761829

Variant names:

• chr12-51687181-C-T
• rs4761829
• NM_001330260.2:c.576C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-51687181-C-T
• chr12-51687181-C-A

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.576C>T​(p.Asp192Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.853 in 1,612,864 control chromosomes in the GnomAD database, including 590,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (51038 hom., cov: 31)
  • Exomes 𝑓: 0.86 (539464 hom.)
• Consequence: SCN8A NM_001330260.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.821
• Publications: 23 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=-0.47).
• BP6: Variant 12-51687181-C-T is Benign according to our data. Variant chr12-51687181-C-T is described in ClinVar as Benign. ClinVar VariationId is 130253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.821 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 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.576C>T	p.Asp192Asp	synonymous	Exon 5 of 27	NP_001317189.1	Q9UQD0-2
	SCN8A	NM_014191.4	MANE Plus Clinical	c.576C>T	p.Asp192Asp	synonymous	Exon 5 of 27	NP_055006.1	Q9UQD0-1
	SCN8A	NM_001177984.3		c.576C>T	p.Asp192Asp	synonymous	Exon 5 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.576C>T	p.Asp192Asp	synonymous	Exon 5 of 27	ENSP00000346534.4	Q9UQD0-1
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.576C>T	p.Asp192Asp	synonymous	Exon 5 of 27	ENSP00000487583.2	Q9UQD0-2
	SCN8A	ENST00000599343.5	TSL:5	c.576C>T	p.Asp192Asp	synonymous	Exon 4 of 26	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123333 AN: 151978 Hom.: 50974 Cov.: 31

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.922

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.688

Gnomad FIN AF: 0.918

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.872

Gnomad OTH AF: 0.831

GnomAD2 exomes AF: 0.848 AC: 211106 AN: 249070 AF XY: 0.838

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.918

Gnomad ASJ exome AF: 0.805

Gnomad EAS exome AF: 0.991

Gnomad FIN exome AF: 0.914

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.848

GnomAD4 exome AF: 0.857 AC: 1251595 AN: 1460768 Hom.: 539464 Cov.: 41 AF XY: 0.851 AC XY: 618711 AN XY: 726702

African (AFR) AF: 0.645 AC: 21554 AN: 33412

American (AMR) AF: 0.913 AC: 40791 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 21143 AN: 26114

East Asian (EAS) AF: 0.995 AC: 39492 AN: 39690

South Asian (SAS) AF: 0.679 AC: 58535 AN: 86194

European-Finnish (FIN) AF: 0.913 AC: 48735 AN: 53398

Middle Eastern (MID) AF: 0.772 AC: 4449 AN: 5762

European-Non Finnish (NFE) AF: 0.869 AC: 965888 AN: 1111196

Other (OTH) AF: 0.846 AC: 51008 AN: 60326

GnomAD4 genome AF: 0.812 AC: 123455 AN: 152096 Hom.: 51038 Cov.: 31 AF XY: 0.813 AC XY: 60480 AN XY: 74348

African (AFR) AF: 0.654 AC: 27076 AN: 41408

American (AMR) AF: 0.872 AC: 13327 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2723 AN: 3470

East Asian (EAS) AF: 0.993 AC: 5149 AN: 5186

South Asian (SAS) AF: 0.689 AC: 3315 AN: 4814

European-Finnish (FIN) AF: 0.918 AC: 9739 AN: 10608

Middle Eastern (MID) AF: 0.764 AC: 223 AN: 292

European-Non Finnish (NFE) AF: 0.872 AC: 59304 AN: 68016

Other (OTH) AF: 0.833 AC: 1758 AN: 2110

Alfa AF: 0.847 Hom.: 97880

Bravo AF: 0.808

Asia WGS AF: 0.855 AC: 2969 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.47
CADD	Benign	6.9
DANN	Benign	0.89
PhyloP100		-0.82
Mutation Taster		=86/14	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: rs4761829; hg19: chr12-52080965; COSMIC: COSV108184328;