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_001733.7(C1R):​c.902G>C​(p.Arg301Pro) 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_001733.7 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_001733.7
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.902G>C	p.Arg301Pro	missense_variant	Exon 6 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.944G>C	p.Arg315Pro	missense_variant	Exon 6 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.902G>C	p.Arg301Pro	missense_variant	Exon 6 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:2

Aug 23, 2016

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 31, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:1

Oct 13, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.52	T;.;T;T
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.27
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	.;.;N;N
REVEL	Benign	0.20
Sift	Benign	0.051	.;.;T;D
Sift4G	Benign	0.076	.;.;T;.
Polyphen		0.99, 0.94	.;.;D;P
Vest4		0.21, 0.19, 0.22
MutPred		0.71		Gain of ubiquitination at K299 (P = 0.0526);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;