12-7082043-C-G

Variant names:

• chr12-7082043-C-G
• rs773720903
• NM_001733.7:c.1337G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001733.7(C1R):​c.1337G>C​(p.Arg446Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,384,806 control chromosomes in the GnomAD database, with no homozygous occurrence. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R446Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.290
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-7082043-C-G is Benign according to our data. Variant chr12-7082043-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 4085130.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.1337G>C	p.Arg446Pro	missense	Exon 10 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.1379G>C	p.Arg460Pro	missense	Exon 10 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.1337G>C	p.Arg446Pro	missense	Exon 10 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.1490G>C	p.Arg497Pro	missense	Exon 11 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.1409G>C	p.Arg470Pro	missense	Exon 11 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1384806 Hom.: 0 Cov.: 30 AF XY: 0.00000439 AC XY: 3 AN XY: 683324

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078778

Other (OTH) AF: 0.00 AC: 0 AN: 57920

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.0094	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.43	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.1	T
PhyloP100		0.29
PrimateAI	Benign	0.32	T
REVEL	Benign	0.15
Sift4G	Benign	0.31	T
Vest4		0.27
MutPred		0.64		Loss of MoRF binding (P = 0.0132)
MVP		0.49
ClinPred		0.90	D
GERP RS		3.4
gMVP		0.83

Splicing

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

Other links and lift over

dbSNP: rs773720903; hg19: chr12-7189347;