rs199718602

Variant names:

• chr19-14755069-C-T
• rs199718602
• NM_013447.4:c.1475G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_013447.4(ADGRE2):​c.1475G>A​(p.Cys492Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADGRE2 NM_013447.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -1.22
• Publications: 12 publications found

Genes affected

ADGRE2 (HGNC:3337): (adhesion G protein-coupled receptor E2) This gene encodes a member of the class B seven-span transmembrane (TM7) subfamily of G-protein coupled receptors. These proteins are characterized by an extended extracellular region with a variable number of N-terminal epidermal growth factor-like domains coupled to a TM7 domain via a mucin-like spacer domain. The encoded protein is expressed mainly in myeloid cells where it promotes cell-cell adhesion through interaction with chondroitin sulfate chains. This gene is situated in a cluster of related genes on chromosome 19. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

ADGRE2 Gene-Disease associations (from GenCC):

• autosomal dominant vibratory urticaria

  Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-14755069-C-T is Pathogenic according to our data. Variant chr19-14755069-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 222005.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14357004). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRE2	NM_013447.4	c.1475G>A	p.Cys492Tyr	missense_variant	Exon 14 of 21	ENST00000315576.8	NP_038475.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRE2	ENST00000315576.8	c.1475G>A	p.Cys492Tyr	missense_variant	Exon 14 of 21	1	NM_013447.4	ENSP00000319883.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Vibratory urticaria Pathogenic:2

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.024
DANN	Benign	0.68
DEOGEN2	Benign	0.10	T;.;.;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.21	T;T;T;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.0	N;.;.;.;.;.
REVEL	Benign	0.075
Sift	Benign	0.11	T;.;.;.;.;.
Sift4G	Benign	0.11	T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;B;.
Vest4		0.14
MutPred		0.54		Loss of sheet (P = 0.1907);.;.;.;.;.;
MVP		0.13
MPC		0.44
ClinPred		0.034	T
GERP RS		-3.3
Varity_R		0.063
gMVP		0.29
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs199718602; hg19: chr19-14865881;