chr14-77616536-C-T

Variant names:

• chr14-77616536-C-T
• rs1164824967
• NM_004863.4:c.44G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004863.4(SPTLC2):​c.44G>A​(p.Arg15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000326 in 1,535,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SPTLC2 NM_004863.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27979207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTLC2	NM_004863.4	c.44G>A	p.Arg15Gln	missense_variant	Exon 1 of 12	ENST00000216484.7	NP_004854.1
SPTLC2	XM_011537384.3	c.44G>A	p.Arg15Gln	missense_variant	Exon 1 of 10		XP_011535686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTLC2	ENST00000216484.7	c.44G>A	p.Arg15Gln	missense_variant	Exon 1 of 12	1	NM_004863.4	ENSP00000216484.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1383366 Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 2 AN XY: 682946

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: 0.00000278

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 1C Uncertain:1

May 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glutamine at codon 15 of the SPTLC2 protein (p.Arg15Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with SPTLC2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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	0.13
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.21
Sift	Benign	0.10	T
Sift4G	Benign	0.52	T
Polyphen		0.30	B
Vest4		0.30
MutPred		0.34		Gain of catalytic residue at R15 (P = 0.0014);
MVP		0.34
MPC		0.76
ClinPred		0.25	T
GERP RS		3.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.083
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1164824967; hg19: chr14-78082879;