NM_004230.4:c.857T>C

Variant names:

• chr19-10224049-A-G
• rs117064827
• NM_004230.4:c.857T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 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 -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 Benign/Likely_benign. ClinVar VariationId is 506086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.857T>C	p.Val286Ala	missense	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.857T>C	p.Val286Ala	missense	Exon 2 of 2	ENSP00000496438.1
	DNMT1	ENST00000588952.5	TSL:5	c.-401-5180T>C		intron	N/A	ENSP00000467050.1
	DNMT1	ENST00000592342.5	TSL:3	c.-284+7155T>C		intron	N/A	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

GnomAD2 exomes AF: 0.00728 AC: 1784 AN: 245062 AF XY: 0.00746

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 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

African (AFR) AF: 0.000944 AC: 31 AN: 32838

American (AMR) AF: 0.00225 AC: 95 AN: 42302

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 462 AN: 25324

East Asian (EAS) AF: 0.00153 AC: 59 AN: 38602

South Asian (SAS) AF: 0.00335 AC: 271 AN: 80978

European-Finnish (FIN) AF: 0.0127 AC: 631 AN: 49510

Middle Eastern (MID) AF: 0.00265 AC: 15 AN: 5656

European-Non Finnish (NFE) AF: 0.00982 AC: 10743 AN: 1094202

Other (OTH) AF: 0.00765 AC: 451 AN: 58932

GnomAD4 genome AF: 0.00645 AC: 918 AN: 142240 Hom.: 3 Cov.: 33 AF XY: 0.00598 AC XY: 417 AN XY: 69788

African (AFR) AF: 0.00146 AC: 56 AN: 38274

American (AMR) AF: 0.00374 AC: 54 AN: 14432

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 53 AN: 3260

East Asian (EAS) AF: 0.00169 AC: 8 AN: 4726

South Asian (SAS) AF: 0.00478 AC: 21 AN: 4392

European-Finnish (FIN) AF: 0.00766 AC: 79 AN: 10318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00997 AC: 636 AN: 63776

Other (OTH) AF: 0.00569 AC: 11 AN: 1934

Alfa AF: 0.00915 Hom.: 27

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.3
PrimateAI	Uncertain	0.61	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	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
Mutation Taster		=81/19	polymorphism

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: rs117064827; hg19: chr19-10334725;