chr12-7089628-C-T

Variant names:

• chr12-7089628-C-T
• rs200018198
• NM_001733.7:c.530G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001733.7(C1R):​c.530G>A​(p.Arg177His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 780,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.14

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17425132).
• BP6: Variant 12-7089628-C-T is Benign according to our data. Variant chr12-7089628-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3769288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.530G>A	p.Arg177His	missense_variant	Exon 4 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.572G>A	p.Arg191His	missense_variant	Exon 4 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.530G>A	p.Arg177His	missense_variant	Exon 4 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000133 AC: 33 AN: 248534 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 134814

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000214

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000159 AC: 100 AN: 628572 Hom.: 0 Cov.: 0 AF XY: 0.000158 AC XY: 54 AN XY: 342412

Gnomad4 AFR exome AF: 0.000113

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000941

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.0000302

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74354

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000241 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000243 AC: 1

ESP6500EA AF: 0.000835 AC: 7

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: C1R c.530G>A (p.Arg177His) results in a non-conservative amino acid change located in the Calcium-binding EGF-like domain (IPR001881) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 248534 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 210 fold of the estimated maximal expected allele frequency for a pathogenic variant in C1R causing Ehlers-Danlos syndrome, periodontal type 1 phenotype (1e-06). To our knowledge, no occurrence of c.530G>A in individuals affected with Ehlers-Danlos syndrome, periodontal type 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	5.0
DANN	Benign	0.95
DEOGEN2	Uncertain	0.51	.;.;D;T;D;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.75	T;.;T;T;T;T
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.9	.;.;D;D;D;D
REVEL	Benign	0.20
Sift	Benign	0.053	.;.;T;D;D;D
Sift4G	Benign	0.33	.;.;T;.;.;.
Polyphen		0.027, 0.14	.;.;B;B;.;.
Vest4		0.16, 0.15, 0.20
MVP		0.57
ClinPred		0.024	T
GERP RS		-2.0
gMVP		0.42

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200018198; hg19: chr12-7242224; COSMIC: COSV105070644; COSMIC: COSV105070644;