14-77552173-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004863.4(SPTLC2):​c.1226C>A​(p.Thr409Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T409T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SPTLC2
NM_004863.4 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.15
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPTLC2NM_004863.4 linkuse as main transcriptc.1226C>A p.Thr409Lys missense_variant 9/12 ENST00000216484.7 NP_004854.1 O15270A0A024R6H1
SPTLC2XM_011537384.3 linkuse as main transcriptc.1226C>A p.Thr409Lys missense_variant 9/10 XP_011535686.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPTLC2ENST00000216484.7 linkuse as main transcriptc.1226C>A p.Thr409Lys missense_variant 9/121 NM_004863.4 ENSP00000216484.2 O15270

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 1C Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 20, 2017This sequence change replaces threonine with lysine at codon 409 of the SPTLC2 protein (p.Thr409Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SPTLC2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.94
D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Uncertain
2.2
M
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.3
D
REVEL
Pathogenic
0.71
Sift
Benign
0.26
T
Sift4G
Benign
0.27
T
Polyphen
0.88
P
Vest4
0.77
MutPred
0.70
Gain of catalytic residue at Y407 (P = 2e-04);
MVP
0.78
MPC
1.1
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.40
gMVP
0.97

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: rs368357970; hg19: chr14-78018516; API