12-7089608-C-T

Position:

• chr12-7089608-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1R	NM_001733.7	c.550G>A	p.Glu184Lys	missense_variant	4/11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.592G>A	p.Glu198Lys	missense_variant	4/11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.550G>A	p.Glu184Lys	missense_variant	4/11		NM_001733.7	ENSP00000497341	P1

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

GnomAD3 exomes AF: 0.114 AC: 28449 AN: 248486 Hom.: 2468 AF XY: 0.116 AC XY: 15698 AN XY: 134820

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 SAS exome AF: 0.158

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

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.0577

Gnomad4 ASJ exome AF: 0.0826

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.0744

Gnomad4 NFE exome AF: 0.0870

Gnomad4 OTH exome AF: 0.116

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

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0712

Gnomad4 ASJ AF: 0.0844

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.0715

Gnomad4 NFE AF: 0.0886

Gnomad4 OTH AF: 0.120

Alfa AF: 0.0983 Hom.: 1532

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.15	T;.;T;T;T
MetaRNN	Benign	0.021	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.34	.;.;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.99	.;.;T;T;T
Sift4G	Benign	0.56	.;.;T;.;.
Polyphen		0.0	.;.;B;B;.
Vest4		0.036, 0.033, 0.16
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

Publications

LitVar

Other links and lift over

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