19-10222312-C-T

Variant names:

• chr19-10222312-C-T
• rs10409243
• NM_004230.4:c.*1532G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004230.4(S1PR2):​c.*1532G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 151,832 control chromosomes in the GnomAD database, including 19,261 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (19249 hom., cov: 30)
  • Exomes 𝑓: 0.55 (12 hom.)
• Consequence: S1PR2 NM_004230.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 33 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.575 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.*1532G>A		3_prime_UTR	Exon 2 of 2	NP_004221.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S1PR2	ENST00000646641.1	MANE Select	c.*1532G>A		3_prime_UTR	Exon 2 of 2	ENSP00000496438.1	O95136
	DNMT1	ENST00000588952.5	TSL:5	c.-401-3443G>A		intron	N/A	ENSP00000467050.1	K7ENQ6
	DNMT1	ENST00000592342.5	TSL:3	c.-284+8892G>A		intron	N/A	ENSP00000465993.1	K7ELB1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 74858 AN: 151636 Hom.: 19255 Cov.: 30

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.546

GnomAD4 exome AF: 0.551 AC: 43 AN: 78 Hom.: 12 Cov.: 0 AF XY: 0.550 AC XY: 22 AN XY: 40

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.516 AC: 32 AN: 62

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.714 AC: 10 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.493 AC: 74872 AN: 151754 Hom.: 19249 Cov.: 30 AF XY: 0.486 AC XY: 36010 AN XY: 74148

African (AFR) AF: 0.386 AC: 15976 AN: 41394

American (AMR) AF: 0.472 AC: 7191 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2213 AN: 3470

East Asian (EAS) AF: 0.250 AC: 1289 AN: 5146

South Asian (SAS) AF: 0.502 AC: 2410 AN: 4800

European-Finnish (FIN) AF: 0.440 AC: 4628 AN: 10508

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.580 AC: 39344 AN: 67890

Other (OTH) AF: 0.546 AC: 1154 AN: 2112

Alfa AF: 0.564 Hom.: 50198

Bravo AF: 0.493

Asia WGS AF: 0.391 AC: 1362 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.4
DANN	Benign	0.66
PhyloP100		-0.052

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: rs10409243; hg19: chr19-10332988;