rs1057518643

Variant names:

• chr12-7088886-T-C
• rs1057518643
• NM_001733.7:c.869A>G
• C1R p.Asp290Gly

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001733.7(C1R):​c.869A>G​(p.Asp290Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.07
• Publications: 3 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]

C1R Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, periodontal type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• autosomal systemic lupus erythematosus type 16

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ehlers-Danlos syndrome, periodontitis type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a mutagenesis_site Decreased association with the C1Q subcomplex. (size 0) in uniprot entity C1R_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 12-7088886-T-C is Pathogenic according to our data. Variant chr12-7088886-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 267356.Status of the report is criteria_provided_single_submitter, 1 stars.

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.869A>G	p.Asp290Gly	missense	Exon 6 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.911A>G	p.Asp304Gly	missense	Exon 6 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.869A>G	p.Asp290Gly	missense	Exon 6 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.1022A>G	p.Asp341Gly	missense	Exon 7 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.941A>G	p.Asp314Gly	missense	Exon 7 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Ehlers-Danlos syndrome, periodontal type 1 (2)
1	-	-	Ehlers-Danlos syndrome, periodontal type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.76	T
PhyloP100		7.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.61
Sift	Benign	0.042	D
Sift4G	Pathogenic	0.0	D
PromoterAI		0.087	Neutral
gMVP		0.95

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057518643;

hg19: chr12-7241482;