rs117064827

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant cerebellar ataxia, deafness and narcolepsy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
hereditary sensory neuropathy-deafness-dementia syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

DNMT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 506086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.00728

AC:

1784

AN:

245062

AF XY:

0.00746

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 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

African (AFR)

AF:

0.000944

AC:

AN:

32838

American (AMR)

AF:

0.00225

AC:

AN:

42302

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

462

AN:

25324

East Asian (EAS)

AF:

0.00153

AC:

AN:

38602

South Asian (SAS)

AF:

0.00335

AC:

271

AN:

80978

European-Finnish (FIN)

AF:

0.0127

AC:

631

AN:

49510

Middle Eastern (MID)

AF:

0.00265

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00982

AC:

10743

AN:

1094202

Other (OTH)

AF:

0.00765

AC:

451

AN:

58932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

805

1610

2415

3220

4025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

398

796

1194

1592

1990

<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

AF:

0.00645

AC:

918

AN:

142240

Hom.:

Cov.:

AF XY:

0.00598

AC XY:

417

AN XY:

69788

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

38274

American (AMR)

AF:

0.00374

AC:

AN:

14432

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

AN:

3260

East Asian (EAS)

AF:

0.00169

AC:

AN:

4726

South Asian (SAS)

AF:

0.00478

AC:

AN:

4392

European-Finnish (FIN)

AF:

0.00766

AC:

AN:

10318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.00997

AC:

636

AN:

63776

Other (OTH)

AF:

0.00569

AC:

AN:

1934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00915

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

S1PR2: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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

PhyloP100

9.3

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

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over