12-7088721-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001733.7(C1R):​c.927C>A​(p.Cys309*) variant causes a stop gained 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.514
• Publications: 0 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: Genomics England PanelApp, G2P, 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.927C>A	p.Cys309*	stop_gained	Exon 7 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.969C>A	p.Cys323*	stop_gained	Exon 7 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.927C>A	p.Cys309*	stop_gained	Exon 7 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.1080C>A	p.Cys360*	stop_gained	Exon 8 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.999C>A	p.Cys333*	stop_gained	Exon 8 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 243498 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		0.51
Vest4		0.98
GERP RS		2.9
PromoterAI		-0.0044	Neutral
Mutation Taster		=100/0	polymorphism

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;