rs1057519578

Variant names:

• chr12-7086404-C-G
• rs1057519578
• NM_001733.7:c.1092G>C
• C1R p.Trp364Cys

Your query was ambiguous. Multiple possible variants found:

• chr12-7086404-C-G
• chr12-7086404-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.1092G>C​(p.Trp364Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.05
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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 disulfide_bond (size 33) in uniprot entity C1R_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001733.7
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-7086404-C-G is Pathogenic according to our data. Variant chr12-7086404-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 375579.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001733.7. 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.1092G>C	p.Trp364Cys	missense	Exon 8 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.1134G>C	p.Trp378Cys	missense	Exon 8 of 11	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.1092G>C	p.Trp364Cys	missense	Exon 8 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.1245G>C	p.Trp415Cys	missense	Exon 9 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.1164G>C	p.Trp388Cys	missense	Exon 9 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ehlers-Danlos syndrome, periodontal type 1 (1)
1	-	-	Ehlers-Danlos syndrome, periodontal type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CADD	Pathogenic	32
DEOGEN2	Benign	0.068	T
LIST_S2	Uncertain	0.95	D
MetaRNN	Uncertain	0.74	D
PhyloP100		6.1
Sift4G	Uncertain	0.0040	D
gMVP		0.82

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057519578;