12-7089608-C-G

Variant names:

• chr12-7089608-C-G
• rs1126605
• NM_001733.7:c.550G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/17 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 Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459
• Publications: 21 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001733.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	NM_001733.7	MANE Select	c.550G>C	p.Glu184Gln	missense	Exon 4 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.592G>C	p.Glu198Gln	missense	Exon 4 of 11	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.550G>C	p.Glu184Gln	missense	Exon 4 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.703G>C	p.Glu235Gln	missense	Exon 5 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.622G>C	p.Glu208Gln	missense	Exon 5 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.045	D
PhyloP100		-0.46
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.22
Sift	Benign	0.59	T
Sift4G	Benign	0.22	T
Polyphen		0.17	B
Vest4		0.040
MutPred		0.54		Loss of disorder (P = 0.2494)
MVP		0.60
ClinPred		0.053	T
GERP RS		-5.2
gMVP		0.34
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

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