Variant 12-7088853-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -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. 12/14 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1R	NM_001733.7 linkuse as main transcript	c.902G>A	p.Arg301His	missense_variant	6/11	ENST00000647956.2
C1R	NM_001354346.2 linkuse as main transcript	c.944G>A	p.Arg315His	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2 linkuse as main transcript	c.902G>A	p.Arg301His	missense_variant	6/11		NM_001733.7	P1

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

GnomAD3 exomes

AF:

0.00000414

AC:

AN:

241274

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130844

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000278

Gnomad4 SAS exome

AF:

0.0000291

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000288

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000333

AC:

AN:

150366

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

73374

show subpopulations

Gnomad4 AFR

AF:

0.0000491

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000948

Gnomad4 NFE

AF:

0.0000296

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.14

DANN

Benign

0.76

DEOGEN2

Benign

0.0050

.;.;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.65

T;.;T;T

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

1.3

.;.;N;N

REVEL

Benign

0.11

Sift

Benign

1.0

.;.;T;T

Sift4G

Benign

0.92

.;.;T;.

Polyphen

0.0040, 0.0020

.;.;B;B

Vest4

0.062, 0.054, 0.089

MutPred

0.69

Gain of methylation at K299 (P = 0.0641);Gain of methylation at K299 (P = 0.0641);.;.;

MVP

0.11

ClinPred

0.76

GERP RS

-10

gMVP

0.23

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over