NM_004230.4:c.857T>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004230.4(S1PR2):c.857T>C(p.Val286Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00871 in 1,570,584 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0089 ( 78 hom. )

Consequence

S1PR2
NM_004230.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

S1PR2 (HGNC:3169): (sphingosine-1-phosphate receptor 2) This gene encodes a member of the G protein-coupled receptors, as well as the EDG family of proteins. The encoded protein is a receptor for sphingosine 1-phosphate, which participates in cell proliferation, survival, and transcriptional activation. Defects in this gene have been associated with congenital profound deafness. [provided by RefSeq, Mar 2016]

S1PR2 links:

DNMT1 (HGNC:2976): (DNA methyltransferase 1) This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DNMT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013470501).

BP6

Variant 19-10224049-A-G is Benign according to our data. Variant chr19-10224049-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 506086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10224049-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S1PR2	NM_004230.4 link	c.857T>C	p.Val286Ala	missense_variant	Exon 2 of 2	ENST00000646641.1	NP_004221.3	O95136A0A024R7B2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
S1PR2	ENST00000646641.1 link	c.857T>C	p.Val286Ala	missense_variant	Exon 2 of 2		NM_004230.4	ENSP00000496438.1	O95136
DNMT1	ENST00000588952.5 link	c.-401-5180T>C		intron_variant	Intron 1 of 8	5		ENSP00000467050.1	K7ENQ6
DNMT1	ENST00000592342.5 link	c.-284+7155T>C		intron_variant	Intron 1 of 6	3		ENSP00000465993.1	K7ELB1

Frequencies

GnomAD3 genomes

AF:

0.00646

AC:

918

AN:

142118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00375

Gnomad ASJ

AF:

0.0163

Gnomad EAS

AF:

0.00169

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00766

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00997

Gnomad OTH

AF:

0.00576

GnomAD3 exomes

AF:

0.00728

AC:

1784

AN:

245062

Hom.:

AF XY:

0.00746

AC XY:

993

AN XY:

133140

show subpopulations

Gnomad AFR exome

AF:

0.00151

Gnomad AMR exome

AF:

0.00216

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.00209

Gnomad SAS exome

AF:

0.00335

Gnomad FIN exome

AF:

0.0107

Gnomad NFE exome

AF:

0.00984

Gnomad OTH exome

AF:

0.00769

GnomAD4 exome

AF:

0.00893

AC:

12758

AN:

1428344

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

6180

AN XY:

710202

show subpopulations

Gnomad4 AFR exome

AF:

0.000944

Gnomad4 AMR exome

AF:

0.00225

Gnomad4 ASJ exome

AF:

0.0182

Gnomad4 EAS exome

AF:

0.00153

Gnomad4 SAS exome

AF:

0.00335

Gnomad4 FIN exome

AF:

0.0127

Gnomad4 NFE exome

AF:

0.00982

Gnomad4 OTH exome

AF:

0.00765

GnomAD4 genome

AF:

0.00645

AC:

918

AN:

142240

Hom.:

Cov.:

AF XY:

0.00598

AC XY:

417

AN XY:

69788

show subpopulations

Gnomad4 AFR

AF:

0.00146

Gnomad4 AMR

AF:

0.00374

Gnomad4 ASJ

AF:

0.0163

Gnomad4 EAS

AF:

0.00169

Gnomad4 SAS

AF:

0.00478

Gnomad4 FIN

AF:

0.00766

Gnomad4 NFE

AF:

0.00997

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00966

Hom.:

Bravo

AF:

0.00561

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00895

AC:

ExAC

AF:

0.00706

AC:

857

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00850

EpiControl

AF:

0.00860

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

S1PR2: BS2 -

not specified

Benign:2

Feb 04, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val286Ala in exon 2 of S1PR2: This variant is not expected to have clinical si gnificance because it has been identified in 1.03% (663/64316) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs117064827). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

.;D

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Uncertain

0.61

Sift4G

Uncertain

0.0030

D;.

Polyphen

0.96

D;D

Vest4

0.54

MVP

0.70

MPC

1.5

ClinPred

0.012

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.72

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