rs1554939509

Positions:

• chr11-33710323-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000611.6(CD59):​c.190T>G​(p.Cys64Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CD59 NM_000611.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50

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]

ENSG00000284969 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD59	NM_000611.6	c.190T>G	p.Cys64Gly	missense_variant	4/4	ENST00000642928.2	NP_000602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD59	ENST00000642928.2	c.190T>G	p.Cys64Gly	missense_variant	4/4		NM_000611.6	ENSP00000494884.1
ENSG00000284969	ENST00000534312.5	c.190T>G	p.Cys64Gly	missense_variant	3/4	3		ENSP00000432362.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary CD59 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.90	.;D;D;D;D;D;D;D;D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.47	T;.;.;.;.;.;.;.;.;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.8	.;M;M;M;M;M;M;M;M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-9.2	D;.;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;D;D;D;D;D;.
Vest4		0.85
MutPred		0.87		Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);Loss of methylation at K63 (P = 0.0152);
MVP		0.99
MPC		0.76
ClinPred		1.0	D
GERP RS		4.4
Varity_R		1.0

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

LitVar

Other links and lift over

dbSNP: rs1554939509; hg19: chr11-33731869;