rs75565823

Positions:

chr14-77576892-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004863.4(SPTLC2):c.506G>C(p.Gly169Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,614,028 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 5 hom. )

Consequence

SPTLC2
NM_004863.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.35

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009984225).

BP6

Variant 14-77576892-C-G is Benign according to our data. Variant chr14-77576892-C-G is described in ClinVar as [Benign]. Clinvar id is 314678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00405 (616/152158) while in subpopulation AFR AF= 0.0134 (556/41500). AF 95% confidence interval is 0.0125. There are 7 homozygotes in gnomad4. There are 292 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 616 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTLC2	NM_004863.4 linkuse as main transcript	c.506G>C	p.Gly169Ala	missense_variant	4/12	ENST00000216484.7	NP_004854.1
SPTLC2	XM_011537384.3 linkuse as main transcript	c.506G>C	p.Gly169Ala	missense_variant	4/10		XP_011535686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTLC2	ENST00000216484.7 linkuse as main transcript	c.506G>C	p.Gly169Ala	missense_variant	4/12	1	NM_004863.4	ENSP00000216484	P1

Frequencies

GnomAD3 genomes

AF:

0.00405

AC:

616

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00341

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00120

AC:

301

AN:

251460

Hom.:

AF XY:

0.00104

AC XY:

142

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000426

AC:

623

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.00132

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:

0.0000549

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.00405

AC:

616

AN:

152158

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

292

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0134

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000626

Hom.:

Bravo

AF:

0.00465

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00137

AC:

166

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 1C

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.38

DEOGEN2

Benign

0.18

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.46

MutationAssessor

Benign

-0.46

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.46

REVEL

Uncertain

0.30

Sift

Benign

0.61

Sift4G

Benign

0.75

Polyphen

0.16

Vest4

0.33

MVP

0.31

MPC

0.56

ClinPred

0.028

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

gMVP

0.59

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over