rs116822112
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_004863.4(SPTLC2):c.977G>A(p.Arg326His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
SPTLC2
NM_004863.4 missense
NM_004863.4 missense
Scores
4
7
8
Clinical Significance
Conservation
PhyloP100: 7.73
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 -4 ACMG points.
BS2
?
High AC in GnomAd4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPTLC2 | NM_004863.4 | c.977G>A | p.Arg326His | missense_variant | 8/12 | ENST00000216484.7 | |
SPTLC2 | XM_011537384.3 | c.977G>A | p.Arg326His | missense_variant | 8/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPTLC2 | ENST00000216484.7 | c.977G>A | p.Arg326His | missense_variant | 8/12 | 1 | NM_004863.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152082Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251398Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135886
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GnomAD4 exome AF: 0.000114 AC: 166AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.000105 AC XY: 76AN XY: 727244
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74402
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuropathy, hereditary sensory and autonomic, type 1C Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 326 of the SPTLC2 protein (p.Arg326His). This variant is present in population databases (rs116822112, gnomAD 0.005%). 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: 579155). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 05, 2022 | The SPTLC2 c.977G>A; p.Arg326His variant (rs116822112), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 579155). This variant is found in the non-Finnish European population with an allele frequency of 0.0053% (6/113,698 alleles) in the Genome Aggregation Database. The arginine at codon 326 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.565). Due to limited information, the clinical significance of this variant is uncertain at this time. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2022 | The p.R326H variant (also known as c.977G>A), located in coding exon 8 of the SPTLC2 gene, results from a G to A substitution at nucleotide position 977. The arginine at codon 326 is replaced by histidine, 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
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
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