Genetic Variant CD59:c.-18-2427G>C (chr11-33724890-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000611.6(CD59):c.-18-2427G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 151,274 control chromosomes in the GnomAD database, including 37,617 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 37617 hom., cov: 29)

Consequence

CD59
NM_000611.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.18

Publications

11 publications found

Variant links:

Genes affected

CD59 (HGNC:1689): (CD59 molecule (CD59 blood group)) This gene encodes a cell surface glycoprotein that regulates complement-mediated cell lysis, and it is involved in lymphocyte signal transduction. This protein is a potent inhibitor of the complement membrane attack complex, whereby it binds complement C8 and/or C9 during the assembly of this complex, thereby inhibiting the incorporation of multiple copies of C9 into the complex, which is necessary for osmolytic pore formation. This protein also plays a role in signal transduction pathways in the activation of T cells. Mutations in this gene cause CD59 deficiency, a disease resulting in hemolytic anemia and thrombosis, and which causes cerebral infarction. Multiple alternatively spliced transcript variants, which encode the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

CD59 Gene-Disease associations (from GenCC):

primary CD59 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

CD59 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CD59	NM_000611.6 link	c.-18-2427G>C	intron_variant	Intron 1 of 3	ENST00000642928.2	NP_000602.1	P13987-1Q6FHM9
CD59	NM_203329.3 link	c.-18-2427G>C	intron_variant	Intron 2 of 4		NP_976074.1	P13987-1Q6FHM9
CD59	NM_203330.2 link	c.-18-2427G>C	intron_variant	Intron 3 of 5		NP_976075.1	P13987-1Q6FHM9
CD59	NM_203331.3 link	c.-18-2427G>C	intron_variant	Intron 2 of 4		NP_976076.1	P13987-1Q6FHM9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD59	ENST00000642928.2 link	c.-18-2427G>C		intron_variant	Intron 1 of 3		NM_000611.6	ENSP00000494884.1		P13987-1

Frequencies

GnomAD3 genomes

AF:

0.691

AC:

104494

AN:

151154

Hom.:

37545

Cov.:

show subpopulations

Gnomad AFR

AF:

0.914

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.612

Gnomad EAS

AF:

0.563

Gnomad SAS

AF:

0.622

Gnomad FIN

AF:

0.644

Gnomad MID

AF:

0.618

Gnomad NFE

AF:

0.617

Gnomad OTH

AF:

0.674

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.692

AC:

104615

AN:

151274

Hom.:

37617

Cov.:

AF XY:

0.686

AC XY:

50686

AN XY:

73904

show subpopulations

African (AFR)

AF:

0.914

AC:

37813

AN:

41384

American (AMR)

AF:

0.541

AC:

8214

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.612

AC:

2108

AN:

3446

East Asian (EAS)

AF:

0.564

AC:

2854

AN:

5058

South Asian (SAS)

AF:

0.623

AC:

2965

AN:

4758

European-Finnish (FIN)

AF:

0.644

AC:

6770

AN:

10514

Middle Eastern (MID)

AF:

0.599

AC:

175

AN:

292

European-Non Finnish (NFE)

AF:

0.617

AC:

41739

AN:

67634

Other (OTH)

AF:

0.677

AC:

1424

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1517

3034

4550

6067

7584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.528

Hom.:

1428

Bravo

AF:

0.689

Asia WGS

AF:

0.630

AC:

2191

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.079

(source)

DANN

Benign

0.40

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over