Genetic Variant NM_001733.7:c.450C>G (chr12-7089708-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001733.7(C1R):c.450C>G(p.Ser150Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000318 in 628,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. 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 Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

C1R
NM_001733.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.686

Publications

0 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 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.099276096).

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.450C>G	p.Ser150Arg	missense	Exon 4 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.492C>G	p.Ser164Arg	missense	Exon 4 of 11	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1R	ENST00000647956.2	MANE Select	c.450C>G	p.Ser150Arg	missense	Exon 4 of 11	ENSP00000497341.1	A0A3B3ISR2
C1R	ENST00000903851.1		c.603C>G	p.Ser201Arg	missense	Exon 5 of 12	ENSP00000573910.1
C1R	ENST00000903850.1		c.522C>G	p.Ser174Arg	missense	Exon 5 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000803

AC:

AN:

249022

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000318

AC:

AN:

628522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17692

American (AMR)

AF:

0.0000457

AC:

AN:

43730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20982

East Asian (EAS)

AF:

0.00

AC:

AN:

36070

South Asian (SAS)

AF:

0.00

AC:

AN:

69798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

349956

Other (OTH)

AF:

0.00

AC:

AN:

33074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.23

CADD

Benign

8.6

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.026

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.59

MetaRNN

Benign

0.099

MetaSVM

Benign

-0.43

PhyloP100

0.69

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.8

REVEL

Benign

0.16

Sift

Benign

0.62

Sift4G

Benign

0.54

Polyphen

0.011

Vest4

0.13

MutPred

0.32

Loss of glycosylation at S150 (P = 0.0402)

MVP

0.83

ClinPred

0.043

GERP RS

4.4

gMVP

0.26

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over