Variant chr19-48626060-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020126.5(SPHK2):c.209C>T(p.Thr70Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,248 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

SPHK2
NM_020126.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.35

Variant links:

Genes affected

SPHK2 (HGNC:18859): (sphingosine kinase 2) This gene encodes one of two sphingosine kinase isozymes that catalyze the phosphorylation of sphingosine into sphingosine 1-phosphate. Sphingosine 1-phosphate mediates many cellular processes including migration, proliferation and apoptosis, and also plays a role in several types of cancer by promoting angiogenesis and tumorigenesis. The encoded protein may play a role in breast cancer proliferation and chemoresistance. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

SPHK2 links:

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ACMG classification

Classification made for transcript

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=0.3533076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPHK2	NM_020126.5 linkuse as main transcript	c.209C>T	p.Thr70Ile	missense_variant	3/7	ENST00000245222.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPHK2	ENST00000245222.9 linkuse as main transcript	c.209C>T	p.Thr70Ile	missense_variant	3/7	1	NM_020126.5	P2	Q9NRA0-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000125

AC:

AN:

248928

Hom.:

AF XY:

0.0000888

AC XY:

AN XY:

135072

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000206

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000143

AC:

209

AN:

1461032

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000118

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2021

The c.209C>T (p.T70I) alteration is located in exon 3 (coding exon 2) of the SPHK2 gene. This alteration results from a C to T substitution at nucleotide position 209, causing the threonine (T) at amino acid position 70 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;T;D;D;T;.;T

Eigen

Benign

0.084

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.82

M_CAP

Benign

0.054

MetaRNN

Benign

0.35

T;T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.4

M;.;M;.;.;.;.

MutationTaster

Benign

0.79

D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.2

D;.;.;.;.;.;.

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;.;.;.;.;.;.

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D

Polyphen

0.98

D;.;D;.;.;.;.

Vest4

0.73

MVP

0.76

MPC

0.83

ClinPred

0.36

GERP RS

2.0

Varity_R

0.33

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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