12-7088721-G-C

Variant names:

• chr12-7088721-G-C
• rs769707492
• NM_001733.7:c.927C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001733.7(C1R):​c.927C>G​(p.Cys309Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C309R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.514
• 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-7088723-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3898059.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 12-7088721-G-C is Pathogenic according to our data. Variant chr12-7088721-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 267353.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.927C>G	p.Cys309Trp	missense_variant	Exon 7 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.969C>G	p.Cys323Trp	missense_variant	Exon 7 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.927C>G	p.Cys309Trp	missense_variant	Exon 7 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

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	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;.;T;T;.
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;.;T;T;T
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
PhyloP100		0.51
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-10	.;.;D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;.;D;D;.
Sift4G	Pathogenic	0.0	.;.;D;.;.
Polyphen		1.0	.;.;D;D;.
Vest4		0.86, 0.89, 0.86
MutPred		0.95		Gain of catalytic residue at P312 (P = 0.0412);Gain of catalytic residue at P312 (P = 0.0412);.;.;.;
MVP		0.47
ClinPred		1.0	D
GERP RS		2.9
PromoterAI		-0.043	Neutral
gMVP		0.95

Splicing

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

Other links and lift over

dbSNP: rs769707492; hg19: chr12-7241317;