rs2116941

Positions:

• chr19-10223767-A-C
• chr19-10223767-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004230.4(S1PR2):​c.*77T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.799 in 1,343,288 control chromosomes in the GnomAD database, including 430,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50004 hom., cov: 32)
  • Exomes 𝑓: 0.80 (380546 hom.)
• Consequence: S1PR2 NM_004230.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.65

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-10223767-A-C is Benign according to our data. Variant chr19-10223767-A-C is described in ClinVar as [Benign]. Clinvar id is 1270177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
S1PR2	NM_004230.4	c.*77T>G		3_prime_UTR_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.*77T>G		3_prime_UTR_variant	2/2		NM_004230.4	ENSP00000496438	P1
DNMT1	ENST00000588952.5	c.-401-4898T>G		intron_variant		5		ENSP00000467050
DNMT1	ENST00000592342.5	c.-284+7437T>G		intron_variant		3		ENSP00000465993

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122846 AN: 152024 Hom.: 49964 Cov.: 32

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.841

GnomAD4 exome AF: 0.798 AC: 950270 AN: 1191146 Hom.: 380546 Cov.: 17 AF XY: 0.799 AC XY: 468698 AN XY: 586804

Gnomad4 AFR exome AF: 0.870

Gnomad4 AMR exome AF: 0.777

Gnomad4 ASJ exome AF: 0.848

Gnomad4 EAS exome AF: 0.586

Gnomad4 SAS exome AF: 0.799

Gnomad4 FIN exome AF: 0.765

Gnomad4 NFE exome AF: 0.805

Gnomad4 OTH exome AF: 0.798

GnomAD4 genome AF: 0.808 AC: 122946 AN: 152142 Hom.: 50004 Cov.: 32 AF XY: 0.805 AC XY: 59886 AN XY: 74368

Gnomad4 AFR AF: 0.866

Gnomad4 AMR AF: 0.795

Gnomad4 ASJ AF: 0.838

Gnomad4 EAS AF: 0.566

Gnomad4 SAS AF: 0.793

Gnomad4 FIN AF: 0.780

Gnomad4 NFE AF: 0.797

Gnomad4 OTH AF: 0.842

Alfa AF: 0.801 Hom.: 60741

Bravo AF: 0.813

Asia WGS AF: 0.709 AC: 2468 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.11
DANN	Benign	0.57

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: rs2116941; hg19: chr19-10334443; COSMIC: COSV58485123;