rs760277934

Variant names:

• chr12-7088853-C-G
• rs760277934
• NM_001733.7:c.902G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-7088853-C-G
• chr12-7088853-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001354346.2(C1R):​c.944G>C​(p.Arg315Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: C1R NM_001354346.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: -0.265
• Publications: 2 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: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 0 uncertain in NM_001354346.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-7088853-C-G is Pathogenic according to our data. Variant chr12-7088853-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 267352.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354346.2. 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.902G>C	p.Arg301Pro	missense	Exon 6 of 11	NP_001724.4
	C1R	NM_001354346.2		c.944G>C	p.Arg315Pro	missense	Exon 6 of 11	NP_001341275.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.902G>C	p.Arg301Pro	missense	Exon 6 of 11	ENSP00000497341.1
	C1R	ENST00000903851.1		c.1055G>C	p.Arg352Pro	missense	Exon 7 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.974G>C	p.Arg325Pro	missense	Exon 7 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

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	0.61
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.52	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.27
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Benign	0.051	T
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.21
MutPred		0.71		Gain of ubiquitination at K299 (P = 0.0526)
MVP		0.17
ClinPred		0.49	T
GERP RS		-10
PromoterAI		0.016	Neutral
gMVP		0.82

Splicing

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

Other links and lift over

dbSNP: rs760277934; hg19: chr12-7241449;