chr12-51721864-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001330260.2(SCN8A):​c.1954A>T​(p.Ile652Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,602,574 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

11
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.98
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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). GenCC has associacion of 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=0.41694623).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN8ANM_001330260.2 linkuse as main transcriptc.1954A>T p.Ile652Phe missense_variant 12/27 ENST00000627620.5 NP_001317189.1 Q9UQD0-2Q6B4S4
SCN8ANM_014191.4 linkuse as main transcriptc.1954A>T p.Ile652Phe missense_variant 12/27 ENST00000354534.11 NP_055006.1 Q9UQD0-1
SCN8ANM_001177984.3 linkuse as main transcriptc.1954A>T p.Ile652Phe missense_variant 12/26 NP_001171455.1 Q9UQD0-5
SCN8ANM_001369788.1 linkuse as main transcriptc.1954A>T p.Ile652Phe missense_variant 12/26 NP_001356717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN8AENST00000354534.11 linkuse as main transcriptc.1954A>T p.Ile652Phe missense_variant 12/271 NM_014191.4 ENSP00000346534.4 Q9UQD0-1
SCN8AENST00000627620.5 linkuse as main transcriptc.1954A>T p.Ile652Phe missense_variant 12/275 NM_001330260.2 ENSP00000487583.2 Q9UQD0-2
SCN8AENST00000599343.5 linkuse as main transcriptc.1954A>T p.Ile652Phe missense_variant 11/265 ENSP00000476447.3 Q9UQD0-3
SCN8AENST00000355133.7 linkuse as main transcriptc.1954A>T p.Ile652Phe missense_variant 11/251 ENSP00000347255.4 Q9UQD0-5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152226
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00000138
AC:
2
AN:
1450348
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
721954
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152226
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 26, 2024The c.1954A>T (p.I652F) alteration is located in exon 12 (coding exon 11) of the SCN8A gene. This alteration results from a A to T substitution at nucleotide position 1954, causing the isoleucine (I) at amino acid position 652 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 30, 2022This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 652 of the SCN8A protein (p.Ile652Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
.;D;.;.;.;.;.
Eigen
Benign
0.029
Eigen_PC
Benign
0.033
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.96
D;D;D;.;D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.42
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.53
D
MutationAssessor
Benign
1.8
.;L;L;L;L;L;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.2
.;N;N;D;.;.;.
REVEL
Uncertain
0.56
Sift
Uncertain
0.0020
.;D;D;D;.;.;.
Sift4G
Benign
0.22
.;T;T;T;T;T;T
Polyphen
0.89, 0.89
.;P;.;.;P;.;.
Vest4
0.52, 0.49, 0.47, 0.61, 0.50
MVP
0.83
MPC
2.0
ClinPred
0.84
D
GERP RS
2.7
Varity_R
0.31
gMVP
0.75

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1048609401; hg19: chr12-52115648; API