rs869312749

Positions:

• chr19-10224583-C-G
• chr19-10224583-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_004230.4(S1PR2):​c.323G>C​(p.Arg108Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: S1PR2 NM_004230.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.88

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-10224583-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant 19-10224583-C-G is Pathogenic according to our data. Variant chr19-10224583-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 219259.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-10224583-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
S1PR2	NM_004230.4	c.323G>C	p.Arg108Pro	missense_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.323G>C	p.Arg108Pro	missense_variant	2/2		NM_004230.4	ENSP00000496438	P1
DNMT1	ENST00000588952.5	c.-401-5714G>C		intron_variant		5		ENSP00000467050
DNMT1	ENST00000592342.5	c.-284+6621G>C		intron_variant		3		ENSP00000465993

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 68 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 19, 2017	- -
Pathogenic, no assertion criteria provided	research	Department of Molecular and Human Genetics, Baylor College of Medicine	Jan 08, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
Sift4G	Uncertain	0.015	D;.
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.73		Gain of glycosylation at S111 (P = 0.1469);Gain of glycosylation at S111 (P = 0.1469);
MVP		0.68
MPC		1.8
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.97

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: rs869312749; hg19: chr19-10335259;