rs2116942

chr19-10223987-T-Achr19-10223987-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_004230.4(S1PR2):c.919A>T(p.Arg307Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,609,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R307R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: S1PR2 NM_004230.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0480

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0047984123).
• BP6: Variant 19-10223987-T-A is Benign according to our data. Variant chr19-10223987-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1210475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
S1PR2	NM_004230.4	c.919A>T	p.Arg307Trp	missense_variant	2/2	ENST00000646641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
S1PR2	ENST00000646641.1	c.919A>T	p.Arg307Trp	missense_variant	2/2		NM_004230.4	P1
DNMT1	ENST00000588952.5	c.-401-5118A>T		intron_variant		5
DNMT1	ENST00000592342.5	c.-284+7217A>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 151994 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00445

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000354 AC: 85 AN: 239966 Hom.: 1 AF XY: 0.000312 AC XY: 41 AN XY: 131394

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00444

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.0000486

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1457070 Hom.: 0 Cov.: 71 AF XY: 0.000121 AC XY: 88 AN XY: 724374

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00349

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.0000572

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74360

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00446

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

ExAC AF: 0.000250 AC: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 07, 2023	- -

S1PR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.055	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
Sift4G	Uncertain	0.017	D;.
Polyphen		0.0	B;B
Vest4		0.28
MutPred		0.49		Loss of disorder (P = 0.006);Loss of disorder (P = 0.006);
MVP		0.28
MPC		0.74
ClinPred		0.035	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.71

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

Other links and lift over

dbSNP: rs2116942; hg19: chr19-10334663;