chr12-7081261-G-A

Variant names:

• chr12-7081261-G-A
• rs147731737
• NM_001733.7:c.1389C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001733.7(C1R):​c.1389C>T​(p.Arg463Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,612,498 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (1 hom.)
• Consequence: C1R NM_001733.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.197
• 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: G2P, PanelApp Australia, Genomics England PanelApp, 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 12-7081261-G-A is Benign according to our data. Variant chr12-7081261-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3768295.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.197 with no splicing effect.
• BS2: High AC in GnomAd4 at 27 AD gene.

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.1389C>T	p.Arg463Arg	synonymous	Exon 11 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.1431C>T	p.Arg477Arg	synonymous	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.1389C>T	p.Arg463Arg	synonymous	Exon 11 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.1542C>T	p.Arg514Arg	synonymous	Exon 12 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.1461C>T	p.Arg487Arg	synonymous	Exon 12 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000615 AC: 15 AN: 243712 AF XY: 0.0000452

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.0000587

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: 0.000336

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1460180 Hom.: 1 Cov.: 35 AF XY: 0.0000220 AC XY: 16 AN XY: 726218

African (AFR) AF: 0.000897 AC: 30 AN: 33450

American (AMR) AF: 0.0000675 AC: 3 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111198

Other (OTH) AF: 0.0000497 AC: 3 AN: 60330

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74478

African (AFR) AF: 0.000625 AC: 26 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.000246

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.5
DANN	Benign	0.49
PhyloP100		0.20

Splicing

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

Other links and lift over

dbSNP: rs147731737; hg19: chr12-7188565;