chr11-19056198-G-C

Position:

• chr11-19056198-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_054030.4(MRGPRX2):​c.205C>G​(p.Leu69Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRGPRX2 NM_054030.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

Genes affected

MRGPRX2 (HGNC:17983): (MAS related GPR family member X2) Enables G protein-coupled receptor activity and neuropeptide binding activity. Involved in mast cell degranulation and positive regulation of cytokinesis. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41325152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRGPRX2	NM_054030.4	c.205C>G	p.Leu69Val	missense_variant	2/2	ENST00000329773.3	NP_473371.1
MRGPRX2	NM_001303615.2	c.205C>G	p.Leu69Val	missense_variant	3/3		NP_001290544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRGPRX2	ENST00000329773.3	c.205C>G	p.Leu69Val	missense_variant	2/2	1	NM_054030.4	ENSP00000333800.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.205C>G (p.L69V) alteration is located in exon 2 (coding exon 1) of the MRGPRX2 gene. This alteration results from a C to G substitution at nucleotide position 205, causing the leucine (L) at amino acid position 69 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.17
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.11
MutPred		0.60		Gain of catalytic residue at L69 (P = 0.1098);
MVP		0.58
MPC		0.56
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.58
gMVP		0.080

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: rs1439188360; hg19: chr11-19077745;