19-10223987-T-G

Variant names:

• chr19-10223987-T-G
• rs2116942
• NM_004230.4:c.919A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0480
• Publications: 19 publications found

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]

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S1PR2	NM_004230.4	c.919A>C	p.Arg307Arg	synonymous_variant	Exon 2 of 2	ENST00000646641.1	NP_004221.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
S1PR2	ENST00000646641.1	c.919A>C	p.Arg307Arg	synonymous_variant	Exon 2 of 2		NM_004230.4	ENSP00000496438.1
DNMT1	ENST00000588952.5	c.-401-5118A>C		intron_variant	Intron 1 of 8	5		ENSP00000467050.1
DNMT1	ENST00000592342.5	c.-284+7217A>C		intron_variant	Intron 1 of 6	3		ENSP00000465993.1

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91661 AN: 151956 Hom.: 28471 Cov.: 33

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

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.: 71 AF XY: 0.579 AC XY: 419520 AN XY: 724116

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

GnomAD4 genome AF: 0.603 AC: 91727 AN: 152074 Hom.: 28491 Cov.: 33 AF XY: 0.594 AC XY: 44172 AN XY: 74338

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

Alfa AF: 0.497 Hom.: 2502

Bravo AF: 0.612

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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.Arg307Arg in exon 2 of S1PR2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 73.32% (6474/8830) o f African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs2116942). -

May 09, 2017

GeneDx

Significance: 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 68 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.4
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)

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

Other links and lift over

dbSNP: rs2116942; hg19: chr19-10334663; COSMIC: COSV58485186;