chr19-10223907-G-A

Variant names:

• chr19-10223907-G-A
• rs764691626
• NM_004230.4:c.999C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_004230.4(S1PR2):​c.999C>T​(p.Ser333Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,442,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: S1PR2 NM_004230.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.09
• 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia, Genomics England PanelApp
• hereditary sensory neuropathy-deafness-dementia syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-10223907-G-A is Benign according to our data. Variant chr19-10223907-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2833717.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-6.09 with no splicing effect.

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.999C>T	p.Ser333Ser	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.999C>T	p.Ser333Ser	synonymous	Exon 2 of 2	ENSP00000496438.1	O95136
	DNMT1	ENST00000588952.5	TSL:5	c.-401-5038C>T		intron	N/A	ENSP00000467050.1	K7ENQ6
	DNMT1	ENST00000592342.5	TSL:3	c.-284+7297C>T		intron	N/A	ENSP00000465993.1	K7ELB1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1442464 Hom.: 0 Cov.: 31 AF XY: 0.00000978 AC XY: 7 AN XY: 715772

African (AFR) AF: 0.0000305 AC: 1 AN: 32798

American (AMR) AF: 0.00 AC: 0 AN: 42494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24674

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 83760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5170

European-Non Finnish (NFE) AF: 0.0000136 AC: 15 AN: 1102232

Other (OTH) AF: 0.0000169 AC: 1 AN: 59334

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.060
DANN	Benign	0.67
PhyloP100		-6.1

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: rs764691626; hg19: chr19-10334583;