dbSNP rs1164824967: SPTLC2:p.Arg15Pro (chr14-77616536-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004863.4(SPTLC2):c.44G>C(p.Arg15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,383,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

SPTLC2
NM_004863.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.87

Publications

0 publications found

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]

SPTLC2 Gene-Disease associations (from GenCC):

neuropathy, hereditary sensory and autonomic, type 1C
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
hereditary sensory and autonomic neuropathy type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPTLC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37267298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTLC2	NM_004863.4 link	c.44G>C	p.Arg15Pro	missense_variant	Exon 1 of 12	ENST00000216484.7	NP_004854.1
SPTLC2	XM_011537384.3 link	c.44G>C	p.Arg15Pro	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 link	c.44G>C	p.Arg15Pro	missense_variant	Exon 1 of 12	1	NM_004863.4	ENSP00000216484.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000289

AC:

AN:

1383366

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

682946

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31468

American (AMR)

AF:

0.00

AC:

AN:

35816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25104

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078518

Other (OTH)

AF:

0.00

AC:

AN:

57844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.0

PhyloP100

1.9

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.92

REVEL

Uncertain

0.55

Sift

Benign

0.040

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.40

MutPred

0.36

Loss of MoRF binding (P = 2e-04);

MVP

0.96

MPC

1.1

ClinPred

0.25

GERP RS

3.1

PromoterAI

0.0072

Neutral

(source)

Varity_R

0.32

gMVP

0.73

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over