Genetic Variant NM_001733.7:c.550G>A (chr12-7089608-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001733.7(C1R):c.550G>A(p.Glu184Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 780,854 control chromosomes in the GnomAD database, including 6,558 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1222 hom., cov: 32)

Exomes 𝑓: 0.11 ( 5336 hom. )

Consequence

C1R
NM_001733.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.459

Publications

21 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020693302).

BP6

Variant 12-7089608-C-T is Benign according to our data. Variant chr12-7089608-C-T is described in ClinVar as Benign. ClinVar VariationId is 1243558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7 link	c.550G>A	p.Glu184Lys	missense_variant	Exon 4 of 11	ENST00000647956.2	NP_001724.4	P00736
C1R	NM_001354346.2 link	c.592G>A	p.Glu198Lys	missense_variant	Exon 4 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2 link	c.550G>A	p.Glu184Lys	missense_variant	Exon 4 of 11		NM_001733.7	ENSP00000497341.1		A0A3B3ISR2

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17210

AN:

152162

Hom.:

1217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.0711

Gnomad ASJ

AF:

0.0844

Gnomad EAS

AF:

0.360

Gnomad SAS

AF:

0.170

Gnomad FIN

AF:

0.0715

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0886

Gnomad OTH

AF:

0.120

GnomAD2 exomes

AF:

0.114

AC:

28449

AN:

248486

AF XY:

0.116

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.0539

Gnomad ASJ exome

AF:

0.0827

Gnomad EAS exome

AF:

0.363

Gnomad FIN exome

AF:

0.0708

Gnomad NFE exome

AF:

0.0878

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.110

AC:

69127

AN:

628574

Hom.:

5336

Cov.:

AF XY:

0.113

AC XY:

38672

AN XY:

342416

show subpopulations

African (AFR)

AF:

0.144

AC:

2554

AN:

17694

American (AMR)

AF:

0.0577

AC:

2523

AN:

43738

Ashkenazi Jewish (ASJ)

AF:

0.0826

AC:

1734

AN:

20982

East Asian (EAS)

AF:

0.355

AC:

12809

AN:

36070

South Asian (SAS)

AF:

0.155

AC:

10826

AN:

69798

European-Finnish (FIN)

AF:

0.0744

AC:

3954

AN:

53112

Middle Eastern (MID)

AF:

0.106

AC:

438

AN:

4148

European-Non Finnish (NFE)

AF:

0.0870

AC:

30460

AN:

349958

Other (OTH)

AF:

0.116

AC:

3829

AN:

33074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

4178

8355

12533

16710

20888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

362

724

1086

1448

1810

<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

AF:

0.113

AC:

17227

AN:

152280

Hom.:

1222

Cov.:

AF XY:

0.115

AC XY:

8569

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.142

AC:

5909

AN:

41552

American (AMR)

AF:

0.0712

AC:

1089

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0844

AC:

293

AN:

3470

East Asian (EAS)

AF:

0.360

AC:

1859

AN:

5162

South Asian (SAS)

AF:

0.170

AC:

822

AN:

4832

European-Finnish (FIN)

AF:

0.0715

AC:

760

AN:

10624

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0886

AC:

6025

AN:

68022

Other (OTH)

AF:

0.120

AC:

253

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

779

1559

2338

3118

3897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.101

Hom.:

3371

Bravo

AF:

0.114

TwinsUK

AF:

0.0917

AC:

340

ALSPAC

AF:

0.0791

AC:

305

ESP6500AA

AF:

0.140

AC:

575

ESP6500EA

AF:

0.0833

AC:

698

ExAC

AF:

0.117

AC:

14164

Asia WGS

AF:

0.207

AC:

717

AN:

3478

EpiCase

AF:

0.0869

EpiControl

AF:

0.0941

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Benign

0.19

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.20

.;.;T;T;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.15

T;.;T;T;T

MetaRNN

Benign

0.021

T;T;T;T;T

MetaSVM

Benign

-0.80

PhyloP100

-0.46

PrimateAI

Benign

0.23

PROVEAN

Benign

0.34

.;.;N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.99

.;.;T;T;T

Sift4G

Benign

0.56

.;.;T;.;.

Polyphen

0.0

.;.;B;B;.

Vest4

0.036, 0.033, 0.16

ClinPred

0.00059

GERP RS

-5.2

gMVP

0.37

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over