Genetic Variant C1R:p.Trp364Cys (chr12-7086404-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1PM1PM2

The NM_001733.7(C1R):c.1092G>T(p.Trp364Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

C1R
NM_001733.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.05

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, periodontal type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
autosomal systemic lupus erythematosus type 16
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ehlers-Danlos syndrome, periodontitis type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

C1R links:

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new If you want to explore the variant's impact on the transcript NM_001733.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PS1

Transcript NM_001733.7 (C1R) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a disulfide_bond (size 33) in uniprot entity C1R_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001733.7

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001733.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	NM_001733.7	MANE Select	c.1092G>T	p.Trp364Cys	missense	Exon 8 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.1134G>T	p.Trp378Cys	missense	Exon 8 of 11	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1R	ENST00000647956.2	MANE Select	c.1092G>T	p.Trp364Cys	missense	Exon 8 of 11	ENSP00000497341.1	A0A3B3ISR2
C1R	ENST00000903851.1		c.1245G>T	p.Trp415Cys	missense	Exon 9 of 12	ENSP00000573910.1
C1R	ENST00000903850.1		c.1164G>T	p.Trp388Cys	missense	Exon 9 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

246400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

124886

African (AFR)

AF:

0.00

AC:

AN:

7182

American (AMR)

AF:

0.00

AC:

AN:

7436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9238

East Asian (EAS)

AF:

0.00

AC:

AN:

22898

South Asian (SAS)

AF:

0.00

AC:

AN:

3036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

158104

Other (OTH)

AF:

0.00

AC:

AN:

16376

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CADD

Pathogenic

(source)

DEOGEN2

Benign

0.068

LIST_S2

Uncertain

0.95

MetaRNN

Uncertain

0.74

PhyloP100

6.1

Sift4G

Uncertain

0.0040

gMVP

0.82

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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C1R p.Trp364Cys

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over