chr12-7088490-T-C

Variant names:

• chr12-7088490-T-C
• rs192083283
• NM_001733.7:c.1038+120A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001733.7(C1R):​c.1038+120A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 715,662 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (6 hom.)
• Consequence: C1R NM_001733.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.135
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-7088490-T-C is Benign according to our data. Variant chr12-7088490-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1694657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 683 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.1038+120A>G		intron	N/A	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.1080+120A>G		intron	N/A	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.1038+120A>G		intron	N/A	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.1191+120A>G		intron	N/A	ENSP00000573910.1
	C1R	ENST00000903850.1		c.1110+120A>G		intron	N/A	ENSP00000573909.1

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 683 AN: 152166 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00587

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00437 AC: 662 AN: 151390 AF XY: 0.00429

Gnomad AFR exome AF: 0.000783

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.00590

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00500 AC: 2816 AN: 563378 Hom.: 6 Cov.: 0 AF XY: 0.00468 AC XY: 1422 AN XY: 304104

African (AFR) AF: 0.00114 AC: 18 AN: 15806

American (AMR) AF: 0.00248 AC: 86 AN: 34718

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 36 AN: 20030

East Asian (EAS) AF: 0.00 AC: 0 AN: 32108

South Asian (SAS) AF: 0.000542 AC: 34 AN: 62772

European-Finnish (FIN) AF: 0.0132 AC: 610 AN: 46178

Middle Eastern (MID) AF: 0.000491 AC: 2 AN: 4070

European-Non Finnish (NFE) AF: 0.00594 AC: 1883 AN: 317016

Other (OTH) AF: 0.00479 AC: 147 AN: 30680

GnomAD4 genome AF: 0.00449 AC: 683 AN: 152284 Hom.: 4 Cov.: 32 AF XY: 0.00505 AC XY: 376 AN XY: 74456

African (AFR) AF: 0.00108 AC: 45 AN: 41554

American (AMR) AF: 0.00255 AC: 39 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0176 AC: 187 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00587 AC: 399 AN: 68014

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00548 Hom.: 2

Bravo AF: 0.00345

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.4
DANN	Benign	0.37
PhyloP100		0.14
PromoterAI		0.030	Neutral

Splicing

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

Other links and lift over

dbSNP: rs192083283; hg19: chr12-7241086; COSMIC: COSV73293825; COSMIC: COSV73293825;