12-7089608-C-G

Position:

• chr12-7089608-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001733.7(C1R):​c.550G>C​(p.Glu184Gln) 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. 13/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E184K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459

Genes affected

C1R (HGNC:1246): (complement C1r) This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

C1RL (HGNC:21265): (complement C1r subcomponent like) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in zymogen activation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10846329).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1R	NM_001733.7	c.550G>C	p.Glu184Gln	missense_variant	4/11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.592G>C	p.Glu198Gln	missense_variant	4/11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.550G>C	p.Glu184Gln	missense_variant	4/11		NM_001733.7	ENSP00000497341	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.30
DANN	Benign	0.50
DEOGEN2	Benign	0.18	.;.;T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.22	T;.;T;T;T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Uncertain	0.045	D
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.24	.;.;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.59	.;.;T;T;T
Sift4G	Benign	0.22	.;.;T;.;.
Polyphen		0.17, 0.19	.;.;B;B;.
Vest4		0.040, 0.048, 0.079
MutPred		0.54		Loss of disorder (P = 0.2494);Loss of disorder (P = 0.2494);.;.;.;
MVP		0.60
ClinPred		0.053	T
GERP RS		-5.2
gMVP		0.34

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1126605; hg19: chr12-7242204; COSMIC: COSV56926324; COSMIC: COSV56926324;