rs143757018
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2
The NM_004863.4(SPTLC2):c.1196G>A(p.Arg399Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
SPTLC2
NM_004863.4 missense
NM_004863.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
SPTLC2 (HGNC:11278): (serine palmitoyltransferase long chain base subunit 2) This gene encodes a long chain base subunit of serine palmitoyltransferase. Serine palmitoyltransferase, which consists of two different subunits, is the key enzyme in sphingolipid biosynthesis. It catalyzes the pyridoxal-5-prime-phosphate-dependent condensation of L-serine and palmitoyl-CoA to 3-oxosphinganine. Mutations in this gene were identified in patients with hereditary sensory neuropathy type I. [provided by RefSeq, Mar 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.93
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000138 (21/152162) while in subpopulation AMR AF= 0.000655 (10/15276). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd4 at 21 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPTLC2 | NM_004863.4 | c.1196G>A | p.Arg399Gln | missense_variant | 9/12 | ENST00000216484.7 | |
SPTLC2 | XM_011537384.3 | c.1196G>A | p.Arg399Gln | missense_variant | 9/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPTLC2 | ENST00000216484.7 | c.1196G>A | p.Arg399Gln | missense_variant | 9/12 | 1 | NM_004863.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251164Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135746
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727200
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GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuropathy, hereditary sensory and autonomic, type 1C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 399 of the SPTLC2 protein (p.Arg399Gln). This variant is present in population databases (rs143757018, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SPTLC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 471487). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPTLC2 protein function with a negative predictive value of 80%. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2022 | The p.R399Q variant (also known as c.1196G>A), located in coding exon 9 of the SPTLC2 gene, results from a G to A substitution at nucleotide position 1196. The arginine at codon 399 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at