rs760459642

Positions:

• chr12-51706681-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_001330260.2(SCN8A):​c.1601A>G​(p.Asn534Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000698 in 1,432,488 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.40

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN8A. . Gene score misZ: 0.78755 (greater than the threshold 3.09). Trascript score misZ: 10.436 (greater than threshold 3.09). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. GenCC has associacion of the gene with myoclonus, familial, 2, infantile convulsions and choreoathetosis, cognitive impairment with or without cerebellar ataxia, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 13, benign familial infantile epilepsy, seizures, benign familial infantile, 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23127636).
• BP6: Variant 12-51706681-A-G is Benign according to our data. Variant chr12-51706681-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 530522.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1601A>G	p.Asn534Ser	missense_variant	11/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1601A>G	p.Asn534Ser	missense_variant	11/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1601A>G	p.Asn534Ser	missense_variant	11/26		NP_001171455.1
SCN8A	NM_001369788.1	c.1601A>G	p.Asn534Ser	missense_variant	11/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1601A>G	p.Asn534Ser	missense_variant	11/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1601A>G	p.Asn534Ser	missense_variant	11/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.1601A>G	p.Asn534Ser	missense_variant	10/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1601A>G	p.Asn534Ser	missense_variant	10/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000447 AC: 1 AN: 223952 Hom.: 0 AF XY: 0.00000824 AC XY: 1 AN XY: 121304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000964

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000698 AC: 10 AN: 1432488 Hom.: 0 Cov.: 31 AF XY: 0.0000113 AC XY: 8 AN XY: 710134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00000727

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	.;D;.;.;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.6	.;L;L;L;L;L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	.;N;N;N;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.16	.;T;T;T;.;.;.
Sift4G	Benign	0.43	.;T;T;T;T;T;T
Polyphen		0.0080, 0.0030	.;B;.;.;B;.;.
Vest4		0.19, 0.18, 0.17, 0.17, 0.17
MutPred		0.29		Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);.;
MVP		0.88
MPC		0.79
ClinPred		0.30	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs760459642; hg19: chr12-52100465;