chr12-7089628-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

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

Scores

3
14

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.14
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]
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]

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ACMG classification

Classification made for transcript

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
C1RNM_001733.7 linkc.530G>A p.Arg177His missense_variant Exon 4 of 11 ENST00000647956.2 NP_001724.4 P00736
C1RNM_001354346.2 linkc.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
C1RENST00000647956.2 linkc.530G>A p.Arg177His missense_variant Exon 4 of 11 NM_001733.7 ENSP00000497341.1 A0A3B3ISR2

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

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

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

Other links and lift over

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