rs774394869

Variant names:

• chr12-7080650-C-A
• rs774394869
• NM_001733.7:c.2000G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-7080650-C-A
• chr12-7080650-C-T

Variant summary

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

The NM_001733.7(C1R):​c.2000G>T​(p.Arg667Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 10/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R667H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• 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.2000G>T	p.Arg667Leu	missense	Exon 11 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.2042G>T	p.Arg681Leu	missense	Exon 11 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.2000G>T	p.Arg667Leu	missense	Exon 11 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.2153G>T	p.Arg718Leu	missense	Exon 12 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.2072G>T	p.Arg691Leu	missense	Exon 12 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249204 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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461710 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.0	T
PhyloP100		-0.014
PrimateAI	Benign	0.28	T
REVEL	Benign	0.089
Sift4G	Uncertain	0.014	D
Vest4		0.39
MutPred		0.83		Loss of MoRF binding (P = 0.085)
MVP		0.30
ClinPred		0.87	D
GERP RS		2.7
gMVP		0.97

Splicing

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

Other links and lift over

dbSNP: rs774394869; hg19: chr12-7187954;