rs1126605

Variant names:

• chr12-7089608-C-T
• rs1126605
• NM_001733.7:c.550G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-7089608-C-T
• chr12-7089608-C-A
• chr12-7089608-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001733.7(C1R):​c.550G>A​(p.Glu184Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 780,854 control chromosomes in the GnomAD database, including 6,558 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1222 hom., cov: 32)
  • Exomes 𝑓: 0.11 (5336 hom.)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.459
• Publications: 21 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]

C1RL (HGNC:21265): (complement C1r subcomponent like) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in zymogen activation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020693302).
• BP6: Variant 12-7089608-C-T is Benign according to our data. Variant chr12-7089608-C-T is described in ClinVar as Benign. ClinVar VariationId is 1243558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

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.550G>A	p.Glu184Lys	missense	Exon 4 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.592G>A	p.Glu198Lys	missense	Exon 4 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.550G>A	p.Glu184Lys	missense	Exon 4 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.703G>A	p.Glu235Lys	missense	Exon 5 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.622G>A	p.Glu208Lys	missense	Exon 5 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17210 AN: 152162 Hom.: 1217 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0886

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.114 AC: 28449 AN: 248486 AF XY: 0.116

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.0539

Gnomad ASJ exome AF: 0.0827

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.0708

Gnomad NFE exome AF: 0.0878

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.110 AC: 69127 AN: 628574 Hom.: 5336 Cov.: 0 AF XY: 0.113 AC XY: 38672 AN XY: 342416

African (AFR) AF: 0.144 AC: 2554 AN: 17694

American (AMR) AF: 0.0577 AC: 2523 AN: 43738

Ashkenazi Jewish (ASJ) AF: 0.0826 AC: 1734 AN: 20982

East Asian (EAS) AF: 0.355 AC: 12809 AN: 36070

South Asian (SAS) AF: 0.155 AC: 10826 AN: 69798

European-Finnish (FIN) AF: 0.0744 AC: 3954 AN: 53112

Middle Eastern (MID) AF: 0.106 AC: 438 AN: 4148

European-Non Finnish (NFE) AF: 0.0870 AC: 30460 AN: 349958

Other (OTH) AF: 0.116 AC: 3829 AN: 33074

GnomAD4 genome AF: 0.113 AC: 17227 AN: 152280 Hom.: 1222 Cov.: 32 AF XY: 0.115 AC XY: 8569 AN XY: 74458

African (AFR) AF: 0.142 AC: 5909 AN: 41552

American (AMR) AF: 0.0712 AC: 1089 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 293 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1859 AN: 5162

South Asian (SAS) AF: 0.170 AC: 822 AN: 4832

European-Finnish (FIN) AF: 0.0715 AC: 760 AN: 10624

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0886 AC: 6025 AN: 68022

Other (OTH) AF: 0.120 AC: 253 AN: 2110

Alfa AF: 0.101 Hom.: 3371

Bravo AF: 0.114

TwinsUK AF: 0.0917 AC: 340

ALSPAC AF: 0.0791 AC: 305

ESP6500AA AF: 0.140 AC: 575

ESP6500EA AF: 0.0833 AC: 698

ExAC AF: 0.117 AC: 14164

Asia WGS AF: 0.207 AC: 717 AN: 3478

EpiCase AF: 0.0869

EpiControl AF: 0.0941

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.19
DANN	Benign	0.60
DEOGEN2	Benign	0.20	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.80	T
PhyloP100		-0.46
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.34	N
REVEL	Uncertain	0.35
Sift	Benign	0.99	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.036
ClinPred		0.00059	T
GERP RS		-5.2
gMVP		0.37

Splicing

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

Other links and lift over

dbSNP: rs1126605; hg19: chr12-7242204; COSMIC: COSV56926434; COSMIC: COSV56926434;