chr12-7090203-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001733.7(C1R):c.277G>T(p.Gly93Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 747,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

C1R
NM_001733.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.73

Variant links:

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 links:

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]

C1RL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15671736).

BS2

High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7 link	c.277G>T	p.Gly93Cys	missense_variant	Exon 3 of 11	ENST00000647956.2	NP_001724.4	P00736
C1R	NM_001354346.2 link	c.319G>T	p.Gly107Cys	missense_variant	Exon 3 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2 link	c.277G>T	p.Gly93Cys	missense_variant	Exon 3 of 11		NM_001733.7	ENSP00000497341.1		A0A3B3ISR2

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000275

AC:

AN:

196396

Hom.:

AF XY:

0.000323

AC XY:

AN XY:

105258

show subpopulations

Gnomad AFR exome

AF:

0.000174

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000106

Gnomad NFE exome

AF:

0.000562

Gnomad OTH exome

AF:

0.000578

GnomAD4 exome

AF:

0.000311

AC:

185

AN:

595408

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

AN XY:

322778

show subpopulations

Gnomad4 AFR exome

AF:

0.000235

Gnomad4 AMR exome

AF:

0.0000260

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000783

Gnomad4 NFE exome

AF:

0.000515

Gnomad4 OTH exome

AF:

0.000157

GnomAD4 genome

AF:

0.000289

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000528

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 30, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 22, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, periodontal type 1

Uncertain:1

Jan 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 12, 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.277G>T (p.Gly93Cys) results in a non-conservative amino acid change located in the CUB domain ( IPR000859) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 196396 control chromosomes. The observed variant frequency is approximately 274 fold of the estimated maximal expected allele frequency for a pathogenic variant in C1R causing Ehlers-Danlos syndrome, periodontal type 1 phenotype (1e-06). c.277G>T has been reported in the literature in individuals affected with periodontal Ehlers-Danlos Syndrome and Purpura fulminans, without strong evidence for causality (Grobner_2019, Bendapudi_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos syndrome, periodontal type 1. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Grobner_2019),. The following publications have been ascertained in the context of this evaluation (PMID: 38096369, 31749804). ClinVar contains an entry for this variant (Variation ID: 597277). 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

0.28

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

.;.;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.87

D;.;D;D

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-0.84

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.4

.;.;N;D

REVEL

Benign

0.18

Sift

Uncertain

0.0080

.;.;D;D

Sift4G

Uncertain

0.0050

.;.;D;.

Polyphen

1.0

.;.;D;.

Vest4

0.58, 0.59

MVP

0.29

ClinPred

0.13

GERP RS

5.3

gMVP

0.50

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over