rs367984544

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BS2

The NM_001330260.2(SCN8A):c.5710C>T(p.Arg1904Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1904H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.786

Publications

2 publications found

Variant links:

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

SCN8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP2

Missense variant in the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.436 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonus, familial, 2, developmental and epileptic encephalopathy, 13, undetermined early-onset epileptic encephalopathy, benign familial infantile epilepsy, complex neurodevelopmental disorder, seizures, benign familial infantile, 5, cognitive impairment with or without cerebellar ataxia, infantile convulsions and choreoathetosis.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2 link	c.5710C>T	p.Arg1904Cys	missense_variant	Exon 27 of 27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 link	c.5710C>T	p.Arg1904Cys	missense_variant	Exon 27 of 27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 link	c.5587C>T	p.Arg1863Cys	missense_variant	Exon 26 of 26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 link	c.5587C>T	p.Arg1863Cys	missense_variant	Exon 26 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 link	c.5710C>T	p.Arg1904Cys	missense_variant	Exon 27 of 27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 link	c.5710C>T	p.Arg1904Cys	missense_variant	Exon 27 of 27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 link	c.5743C>T	p.Arg1915Cys	missense_variant	Exon 26 of 26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 link	c.5587C>T	p.Arg1863Cys	missense_variant	Exon 25 of 25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111864

Other (OTH)

AF:

0.0000331

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000826

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 29, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5710C>T (p.R1904C) alteration is located in exon 27 (coding exon 26) of the SCN8A gene. This alteration results from a C to T substitution at nucleotide position 5710, causing the arginine (R) at amino acid position 1904 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy

Uncertain:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1904 of the SCN8A protein (p.Arg1904Cys). This variant is present in population databases (rs367984544, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of SCN8A-related conditions (PMID: 31335965, 33004838; internal data). This variant is also known as c.5743C>T (p.Arg1915Cys). ClinVar contains an entry for this variant (Variation ID: 530423). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN8A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Complex neurodevelopmental disorder

Uncertain:1

Jan 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in SCN8A is predicted to replace arginine with cysteine at codon 1904, p.(Arg1904Cys). The arginine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the cytoplasmic domain. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.003% (2/60,008 alleles) in the Admixed American population. This variant has been reported in two unrelated individuals with epilepsy phenotypes (PMID: 31887642, 31335965). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.205). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

D;.;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.50

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.6

M;.;.;.;M

PhyloP100

0.79

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.4

D;D;.;.;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.50

MutPred

0.61

Loss of MoRF binding (P = 0.0077);.;.;.;Loss of MoRF binding (P = 0.0077);

MVP

0.57

MPC

2.5

ClinPred

1.0

GERP RS

5.0

Varity_R

0.76

gMVP

0.96

Mutation Taster

=65/35

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over