rs2364602

Positions:

• chr14-77562460-A-C
• chr14-77562460-A-G
• chr14-77562460-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004863.4(SPTLC2):​c.786T>G​(p.Asn262Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N262N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTLC2 NM_004863.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.570

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]

SPTLC2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTLC2	NM_004863.4	c.786T>G	p.Asn262Lys	missense_variant	6/12	ENST00000216484.7	NP_004854.1
SPTLC2	XM_011537384.3	c.786T>G	p.Asn262Lys	missense_variant	6/10		XP_011535686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTLC2	ENST00000216484.7	c.786T>G	p.Asn262Lys	missense_variant	6/12	1	NM_004863.4	ENSP00000216484.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.4	H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.76		Gain of catalytic residue at S258 (P = 0);
MVP		0.63
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

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

Other links and lift over

dbSNP: rs2364602; hg19: chr14-78028803;