rs121964920

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP5BS2

The NM_000587.4(C7):c.1561C>A(p.Arg521Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,611,512 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 15 hom. )

Consequence

C7
NM_000587.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:5

Conservation

PhyloP100: 0.470

Publications

9 publications found

Variant links:

Genes affected

C7 (HGNC:1346): (complement C7) This gene encodes a serum glycoprotein that forms a membrane attack complex together with complement components C5b, C6, C8, and C9 as part of the terminal complement pathway of the innate immune system. The protein encoded by this gene contains a cholesterol-dependent cytolysin/membrane attack complex/perforin-like (CDC/MACPF) domain and belongs to a large family of structurally related molecules that form pores involved in host immunity and bacterial pathogenesis. This protein initiates membrane attack complex formation by binding the C5b-C6 subcomplex and inserts into the phospholipid bilayer, serving as a membrane anchor. Mutations in this gene are associated with a rare disorder called C7 deficiency. [provided by RefSeq, Nov 2016]

C7 Gene-Disease associations (from GenCC):

complement component 7 deficiency
Inheritance: AR Classification: STRONG Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)

C7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP5

Variant 5-40959520-C-A is Pathogenic according to our data. Variant chr5-40959520-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12105.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000587.4. 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
	C7	NM_000587.4	MANE Select	c.1561C>A	p.Arg521Ser	missense	Exon 12 of 18	NP_000578.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C7	ENST00000313164.10	TSL:1 MANE Select	c.1561C>A	p.Arg521Ser	missense	Exon 12 of 18	ENSP00000322061.9	P10643
C7	ENST00000908410.1		c.1705C>A	p.Arg569Ser	missense	Exon 13 of 19	ENSP00000578469.1
C7	ENST00000908412.1		c.1561C>A	p.Arg521Ser	missense	Exon 12 of 19	ENSP00000578471.1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00434

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00233

AC:

574

AN:

246854

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.000525

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000606

Gnomad NFE exome

AF:

0.00421

Gnomad OTH exome

AF:

0.00334

GnomAD4 exome

AF:

0.00318

AC:

4640

AN:

1459306

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

2266

AN XY:

725784

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33418

American (AMR)

AF:

0.00137

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00134

AC:

115

AN:

85938

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00167

AC:

AN:

4778

European-Non Finnish (NFE)

AF:

0.00381

AC:

4237

AN:

1111280

Other (OTH)

AF:

0.00254

AC:

153

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

223

446

669

892

1115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00248

AC:

378

AN:

152206

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41522

American (AMR)

AF:

0.00150

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00270

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000944

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00434

AC:

295

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2114

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

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:

0.00353

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00388

AC:

ExAC

AF:

0.00247

AC:

298

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Complement component 7 deficiency (11)

not provided (4)

C7 and C6 deficiency, combined subtotal (1)

C7-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.14

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

5.0

PhyloP100

0.47

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.72

MPC

0.14

ClinPred

0.15

GERP RS

4.3

Varity_R

0.98

gMVP

0.89

Mutation Taster

=70/30

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over