19-10224727-C-G

Variant names:

• chr19-10224727-C-G
• rs3745268
• NM_004230.4:c.179G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004230.4(S1PR2):​c.179G>C​(p.Arg60Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R60Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: S1PR2 NM_004230.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.01
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S1PR2	NM_004230.4	c.179G>C	p.Arg60Pro	missense_variant	Exon 2 of 2	ENST00000646641.1	NP_004221.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
S1PR2	ENST00000646641.1	c.179G>C	p.Arg60Pro	missense_variant	Exon 2 of 2		NM_004230.4	ENSP00000496438.1
DNMT1	ENST00000588952.5	c.-401-5858G>C		intron_variant	Intron 1 of 8	5		ENSP00000467050.1
DNMT1	ENST00000592342.5	c.-284+6477G>C		intron_variant	Intron 1 of 6	3		ENSP00000465993.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.2	M;M
PhyloP100		5.0
PrimateAI	Uncertain	0.64	T
Sift4G	Uncertain	0.027	D;.
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.79		Loss of methylation at R60 (P = 0.0894);Loss of methylation at R60 (P = 0.0894);
MVP		0.62
MPC		1.8
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.91
Mutation Taster		=16/84	disease causing

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: rs3745268; hg19: chr19-10335403;