rs1057519579

Positions:

• chr12-7086383-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PS1_Moderate PM1 PM2 PP5_Moderate BP4

The NM_001733.7(C1R):​c.1113C>G​(p.Cys371Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_001733.7 (C1R) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a domain Sushi 1 (size 66) in uniprot entity C1R_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_001733.7
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-7086383-G-C is Pathogenic according to our data. Variant chr12-7086383-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 375580.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-7086383-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.30920333). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1R	NM_001733.7	c.1113C>G	p.Cys371Trp	missense_variant	8/11	ENST00000647956.2
C1R	NM_001354346.2	c.1155C>G	p.Cys385Trp	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2	c.1113C>G	p.Cys371Trp	missense_variant	8/11		NM_001733.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Oct 13, 2016

- -

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, Medical University Innsbruck

Aug 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CADD	Pathogenic	30
DEOGEN2	Benign	0.30	.;.;T;T;.
LIST_S2	Benign	0.83	T;.;T;T;T
MetaRNN	Benign	0.31	T;T;T;T;T
PROVEAN	Benign	-1.6	.;N;.;.;.
Sift	Benign	0.041	.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.
Vest4		0.79, 0.79, 0.78
gMVP		0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519579; hg19: -;