12-7081221-A-AGG

Position:

• chr12-7081221-A-AGG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001733.7(C1R):​c.1427_1428dupCC​(p.Trp477fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.600

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-7081221-A-AGG is Pathogenic according to our data. Variant chr12-7081221-A-AGG is described in ClinVar as [Pathogenic]. Clinvar id is 973553.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1R	NM_001733.7	c.1427_1428dupCC	p.Trp477fs	frameshift_variant	11/11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.1469_1470dupCC	p.Trp491fs	frameshift_variant	11/11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.1427_1428dupCC	p.Trp477fs	frameshift_variant	11/11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1938056582; hg19: chr12-7188525;