12-7090203-C-T

Variant names:

• chr12-7090203-C-T
• NM_001733.7:c.277G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001733.7(C1R):​c.277G>A​(p.Gly93Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G93C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19086733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.277G>A	p.Gly93Ser	missense_variant	Exon 3 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.319G>A	p.Gly107Ser	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	c.277G>A	p.Gly93Ser	missense_variant	Exon 3 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 17, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: C1R c.277G>A (p.Gly93Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 196396 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.277G>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 uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	.;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.91	D;.;D;D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.45	.;.;N;D
REVEL	Benign	0.13
Sift	Benign	1.0	.;.;T;T
Sift4G	Benign	0.16	.;.;T;.
Polyphen		0.75	.;.;P;.
Vest4		0.42, 0.44
MutPred		0.48		Gain of catalytic residue at G93 (P = 0.0121);Gain of catalytic residue at G93 (P = 0.0121);.;Gain of catalytic residue at G93 (P = 0.0121);
MVP		0.19
ClinPred		0.96	D
GERP RS		5.3
gMVP		0.32

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7242799;