rs116191851

Variant names:

• chr19-10223856-G-A
• rs116191851
• NM_004230.4:c.1050C>T

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.1050C>T​(p.Asn350Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00501 in 1,541,202 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (185 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (174 hom.)
• Consequence: S1PR2 NM_004230.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.297
• Publications: 0 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=-0.62).
• BP6: Variant 19-10223856-G-A is Benign according to our data. Variant chr19-10223856-G-A is described in ClinVar as Benign. ClinVar VariationId is 506084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.297 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.088 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.1050C>T	p.Asn350Asn	synonymous	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.1050C>T	p.Asn350Asn	synonymous	Exon 2 of 2	ENSP00000496438.1
	DNMT1	ENST00000588952.5	TSL:5	c.-401-4987C>T		intron	N/A	ENSP00000467050.1
	DNMT1	ENST00000592342.5	TSL:3	c.-284+7348C>T		intron	N/A	ENSP00000465993.1

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4019 AN: 152152 Hom.: 185 Cov.: 33

Gnomad AFR AF: 0.0906

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.00812 AC: 1564 AN: 192662 AF XY: 0.00605

Gnomad AFR exome AF: 0.0941

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000597

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00433

GnomAD4 exome AF: 0.00266 AC: 3696 AN: 1388932 Hom.: 174 Cov.: 31 AF XY: 0.00223 AC XY: 1523 AN XY: 683404

African (AFR) AF: 0.0983 AC: 3046 AN: 30998

American (AMR) AF: 0.00522 AC: 180 AN: 34504

Ashkenazi Jewish (ASJ) AF: 0.0000957 AC: 2 AN: 20904

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39140

South Asian (SAS) AF: 0.000214 AC: 16 AN: 74840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50194

Middle Eastern (MID) AF: 0.00508 AC: 22 AN: 4334

European-Non Finnish (NFE) AF: 0.0000882 AC: 95 AN: 1076998

Other (OTH) AF: 0.00584 AC: 333 AN: 57020

GnomAD4 genome AF: 0.0264 AC: 4020 AN: 152270 Hom.: 185 Cov.: 33 AF XY: 0.0262 AC XY: 1953 AN XY: 74460

African (AFR) AF: 0.0904 AC: 3757 AN: 41550

American (AMR) AF: 0.0126 AC: 193 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68012

Other (OTH) AF: 0.0260 AC: 55 AN: 2116

Alfa AF: 0.0221 Hom.: 38

Bravo AF: 0.0305

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	S1PR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.7
DANN	Benign	0.63
PhyloP100		0.30
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: rs116191851; hg19: chr19-10334532;