rs2116941

Variant names:

• chr19-10223767-A-C
• rs2116941
• NM_004230.4:c.*77T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10223767-A-C
• chr19-10223767-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004230.4(S1PR2):​c.*77T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.799 in 1,343,288 control chromosomes in the GnomAD database, including 430,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50004 hom., cov: 32)
  • Exomes 𝑓: 0.80 (380546 hom.)
• Consequence: S1PR2 NM_004230.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.65
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-10223767-A-C is Benign according to our data. Variant chr19-10223767-A-C is described in ClinVar as Benign. ClinVar VariationId is 1270177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S1PR2	NM_004230.4	c.*77T>G		3_prime_UTR_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.*77T>G		3_prime_UTR_variant	Exon 2 of 2		NM_004230.4	ENSP00000496438.1
DNMT1	ENST00000588952.5	c.-401-4898T>G		intron_variant	Intron 1 of 8	5		ENSP00000467050.1
DNMT1	ENST00000592342.5	c.-284+7437T>G		intron_variant	Intron 1 of 6	3		ENSP00000465993.1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122846 AN: 152024 Hom.: 49964 Cov.: 32

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.841

GnomAD4 exome AF: 0.798 AC: 950270 AN: 1191146 Hom.: 380546 Cov.: 17 AF XY: 0.799 AC XY: 468698 AN XY: 586804

African (AFR) AF: 0.870 AC: 23032 AN: 26484

American (AMR) AF: 0.777 AC: 20672 AN: 26592

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 15680 AN: 18480

East Asian (EAS) AF: 0.586 AC: 21771 AN: 37162

South Asian (SAS) AF: 0.799 AC: 50694 AN: 63412

European-Finnish (FIN) AF: 0.765 AC: 36729 AN: 48006

Middle Eastern (MID) AF: 0.879 AC: 2973 AN: 3384

European-Non Finnish (NFE) AF: 0.805 AC: 738751 AN: 917522

Other (OTH) AF: 0.798 AC: 39968 AN: 50104

GnomAD4 genome AF: 0.808 AC: 122946 AN: 152142 Hom.: 50004 Cov.: 32 AF XY: 0.805 AC XY: 59886 AN XY: 74368

African (AFR) AF: 0.866 AC: 35978 AN: 41534

American (AMR) AF: 0.795 AC: 12154 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2911 AN: 3472

East Asian (EAS) AF: 0.566 AC: 2909 AN: 5138

South Asian (SAS) AF: 0.793 AC: 3827 AN: 4826

European-Finnish (FIN) AF: 0.780 AC: 8256 AN: 10578

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.797 AC: 54155 AN: 67988

Other (OTH) AF: 0.842 AC: 1782 AN: 2116

Alfa AF: 0.802 Hom.: 86631

Bravo AF: 0.813

Asia WGS AF: 0.709 AC: 2468 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.11
DANN	Benign	0.57
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs2116941; hg19: chr19-10334443; COSMIC: COSV58485123;