12-7088853-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1PM5BP4_ModerateBS2

The NM_001733.7(C1R):c.902G>A(p.Arg301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 771,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/16 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R301P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

C1R
NM_001733.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.265

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: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 0 uncertain in NM_001733.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-7088853-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 267352.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.17685336).

BS2

High AC in GnomAd4 at 5 AD gene.

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.902G>A	p.Arg301His	missense	Exon 6 of 11	NP_001724.4
	C1R	NM_001354346.2		c.944G>A	p.Arg315His	missense	Exon 6 of 11	NP_001341275.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
C1R	ENST00000647956.2	MANE Select	c.902G>A	p.Arg301His	missense	Exon 6 of 11	ENSP00000497341.1
C1R	ENST00000903851.1		c.1055G>A	p.Arg352His	missense	Exon 7 of 12	ENSP00000573910.1
C1R	ENST00000903850.1		c.974G>A	p.Arg325His	missense	Exon 7 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes

AF:

0.0000333

AC:

AN:

150366

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000491

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:

0.0000948

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000414

AC:

AN:

241274

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000671

Gnomad AMR exome

AF:

0.00

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:

0.00000644

AC:

AN:

621148

Hom.:

Cov.:

AF XY:

0.00000887

AC XY:

AN XY:

338278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17400

American (AMR)

AF:

0.00

AC:

AN:

42816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20600

East Asian (EAS)

AF:

0.0000278

AC:

AN:

35988

South Asian (SAS)

AF:

0.0000291

AC:

AN:

68616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.00000288

AC:

AN:

346964

Other (OTH)

AF:

0.00

AC:

AN:

32744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000333

AC:

AN:

150366

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

73374

show subpopulations

African (AFR)

AF:

0.0000491

AC:

AN:

40746

American (AMR)

AF:

0.00

AC:

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4672

European-Finnish (FIN)

AF:

0.0000948

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

67492

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.595

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.14

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0050

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.65

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

PhyloP100

-0.27

PrimateAI

Benign

0.24

PROVEAN

Benign

1.3

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

0.92

Polyphen

0.0040

Vest4

0.062

MutPred

0.69

Gain of methylation at K299 (P = 0.0641)

MVP

0.11

ClinPred

0.76

GERP RS

-10

PromoterAI

-0.011

Neutral

(source)

gMVP

0.23

Mutation Taster

=97/3

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