12-7090215-A-G

Position:

• chr12-7090215-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001733.7(C1R):​c.265T>C​(p.Cys89Arg) variant causes a missense change involving the alteration of a 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.81

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

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 12-7090215-A-G is Pathogenic according to our data. Variant chr12-7090215-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 972707.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1R	NM_001733.7	c.265T>C	p.Cys89Arg	missense_variant	3/11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.307T>C	p.Cys103Arg	missense_variant	3/11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.265T>C	p.Cys89Arg	missense_variant	3/11		NM_001733.7	ENSP00000497341	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ehlers-Danlos syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Periodontology, Nanjing Stomatological Hospital, Medical School of Nanjing University

Apr 25, 2020

The Cys276Arg variant in C1R has been reported in 1 Chinese families with autosomal dominant associated with severe periodontitis and tooth loss, clinical features suggested a provisional diagnosis of periodontal Ehlers-Danlos syndrome. Whole-exome sequencing identified the Cys276Arg variant in C1R in all affected family members tested (3 affected relatives) and none of the unaffected members (3 relatives) showed genetic findings. The functional context of the Cys276Arg variant in C1R was predicted by sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (Polyphen) v2.0 sharewares: SIFT prediction = 0, deleterious; Polyphen-2 prediction = 0.962, probably damaging. In summary, the Cys276Arg in C1R meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;.;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;.;T;D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-11	.;.;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Benign	0.094	.;.;T;.
Polyphen		0.96	.;.;D;.
Vest4		0.96, 0.96
MutPred		0.97		Gain of disorder (P = 0.0054);Gain of disorder (P = 0.0054);.;Gain of disorder (P = 0.0054);
MVP		0.38
ClinPred		1.0	D
GERP RS		5.3
gMVP		0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1938242419; hg19: chr12-7242811;