rs117064827

Positions:

• chr19-10224049-A-G
• chr19-10224049-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 9.32

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 -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/exons	MANE	Protein	UniProt
S1PR2	NM_004230.4	c.857T>C	p.Val286Ala	missense_variant	2/2	ENST00000646641.1	NP_004221.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
S1PR2	ENST00000646641.1	c.857T>C	p.Val286Ala	missense_variant	2/2		NM_004230.4	ENSP00000496438.1
DNMT1	ENST00000588952.5	c.-401-5180T>C		intron_variant		5		ENSP00000467050.1
DNMT1	ENST00000592342.5	c.-284+7155T>C		intron_variant		3		ENSP00000465993.1

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 918 AN: 142118 Hom.: 3 Cov.: 33

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.: 9 AF XY: 0.00746 AC XY: 993 AN XY: 133140

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.: 78 Cov.: 35 AF XY: 0.00870 AC XY: 6180 AN XY: 710202

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.: 3 Cov.: 33 AF XY: 0.00598 AC XY: 417 AN XY: 69788

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.: 15

Bravo AF: 0.00561

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00706 AC: 857

Asia WGS AF: 0.00318 AC: 11 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

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	S1PR2: BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	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	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.61	T
Sift4G	Uncertain	0.0030	D;.
Polyphen		0.96	D;D
Vest4		0.54
MVP		0.70
MPC		1.5
ClinPred		0.012	T
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

Other links and lift over

dbSNP: rs117064827; hg19: chr19-10334725;