19-10223987-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004230.4(S1PR2):c.919A>C(p.Arg307Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,608,656 control chromosomes in the GnomAD database, including 278,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 28491 hom., cov: 33)

Exomes 𝑓: 0.58 ( 249795 hom. )

Consequence

S1PR2
NM_004230.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0480

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 19-10223987-T-G is Benign according to our data. Variant chr19-10223987-T-G is described in ClinVar as Benign. ClinVar VariationId is 506085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.048 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004230.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S1PR2	NM_004230.4	MANE Select	c.919A>C	p.Arg307Arg	synonymous	Exon 2 of 2	NP_004221.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
S1PR2	ENST00000646641.1	MANE Select	c.919A>C	p.Arg307Arg	synonymous	Exon 2 of 2	ENSP00000496438.1
DNMT1	ENST00000588952.5	TSL:5	c.-401-5118A>C		intron	N/A	ENSP00000467050.1
DNMT1	ENST00000592342.5	TSL:3	c.-284+7217A>C		intron	N/A	ENSP00000465993.1

Frequencies

GnomAD3 genomes

AF:

0.603

AC:

91661

AN:

151956

Hom.:

28471

Cov.:

show subpopulations

Gnomad AFR

AF:

0.734

Gnomad AMI

AF:

0.545

Gnomad AMR

AF:

0.516

Gnomad ASJ

AF:

0.641

Gnomad EAS

AF:

0.306

Gnomad SAS

AF:

0.517

Gnomad FIN

AF:

0.497

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.586

Gnomad OTH

AF:

0.629

GnomAD2 exomes

AF:

0.537

AC:

128942

AN:

239966

AF XY:

0.542

show subpopulations

Gnomad AFR exome

AF:

0.733

Gnomad AMR exome

AF:

0.432

Gnomad ASJ exome

AF:

0.634

Gnomad EAS exome

AF:

0.305

Gnomad FIN exome

AF:

0.494

Gnomad NFE exome

AF:

0.587

Gnomad OTH exome

AF:

0.566

GnomAD4 exome

AF:

0.581

AC:

845901

AN:

1456582

Hom.:

249795

Cov.:

AF XY:

0.579

AC XY:

419520

AN XY:

724116

show subpopulations

African (AFR)

AF:

0.738

AC:

24593

AN:

33322

American (AMR)

AF:

0.436

AC:

19338

AN:

44316

Ashkenazi Jewish (ASJ)

AF:

0.634

AC:

16477

AN:

25980

East Asian (EAS)

AF:

0.314

AC:

12448

AN:

39584

South Asian (SAS)

AF:

0.521

AC:

44834

AN:

86016

European-Finnish (FIN)

AF:

0.493

AC:

25852

AN:

52392

Middle Eastern (MID)

AF:

0.615

AC:

3505

AN:

5700

European-Non Finnish (NFE)

AF:

0.599

AC:

663852

AN:

1109162

Other (OTH)

AF:

0.582

AC:

35002

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

22469

44938

67408

89877

112346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18118

36236

54354

72472

90590

<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:

0.603

AC:

91727

AN:

152074

Hom.:

28491

Cov.:

AF XY:

0.594

AC XY:

44172

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.735

AC:

30505

AN:

41526

American (AMR)

AF:

0.515

AC:

7867

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.641

AC:

2220

AN:

3462

East Asian (EAS)

AF:

0.306

AC:

1577

AN:

5154

South Asian (SAS)

AF:

0.516

AC:

2487

AN:

4822

European-Finnish (FIN)

AF:

0.497

AC:

5239

AN:

10548

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.586

AC:

39824

AN:

67972

Other (OTH)

AF:

0.628

AC:

1327

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1914

3828

5742

7656

9570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<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:

0.497

Hom.:

2502

Bravo

AF:

0.612

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Autosomal recessive nonsyndromic hearing loss 68 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.4

(source)

DANN

Benign

0.38

PhyloP100

-0.048

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over