19-47340909-C-A

Variant names:

• chr19-47340909-C-A
• rs767505747
• NM_001271749.2:c.110C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001271749.2(C5AR2):​c.110C>A​(p.Ala37Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: C5AR2 NM_001271749.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.200

Genes affected

C5AR2 (HGNC:4527): (complement C5a receptor 2) This gene encodes a G-protein coupled receptor 1 family member involved in the complement system of the innate immune response. Unlike classical G-protein coupled receptors, the encoded protein does not associate with intracellular G-proteins. It may instead modulate signal transduction through the beta-arrestin pathway, and may alternatively act as a decoy receptor. This gene may be involved in coronary artery disease and in the pathogenesis of sepsis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5AR2	NM_001271749.2	c.110C>A	p.Ala37Asp	missense_variant	Exon 2 of 2	ENST00000595464.3	NP_001258678.1
C5AR2	NM_001271750.2	c.110C>A	p.Ala37Asp	missense_variant	Exon 2 of 2		NP_001258679.1
C5AR2	NM_018485.3	c.110C>A	p.Ala37Asp	missense_variant	Exon 2 of 2		NP_060955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5AR2	ENST00000595464.3	c.110C>A	p.Ala37Asp	missense_variant	Exon 2 of 2	1	NM_001271749.2	ENSP00000472620.1
C5AR2	ENST00000600626.1	c.110C>A	p.Ala37Asp	missense_variant	Exon 2 of 2	1		ENSP00000471184.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460506 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726634

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.110C>A (p.A37D) alteration is located in exon 2 (coding exon 1) of the C5AR2 gene. This alteration results from a C to A substitution at nucleotide position 110, causing the alanine (A) at amino acid position 37 to be replaced by an aspartic acid (D). 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.42	.;T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Benign	0.35	T
Sift4G	Uncertain	0.035	D;D
Polyphen		0.53	P;P
Vest4		0.62
MutPred		0.50		Gain of phosphorylation at Y42 (P = 0.1652);Gain of phosphorylation at Y42 (P = 0.1652);
MVP		0.27
MPC		0.43
ClinPred		0.18	T
GERP RS		-0.060
Varity_R		0.22
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs767505747; hg19: chr19-47844166;