rs397514767

chr11-33710247-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000611.6(CD59):c.266G>A(p.Cys89Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C89C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CD59 NM_000611.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.92

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-33710247-C-T is Pathogenic according to our data. Variant chr11-33710247-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 64690.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-33710247-C-T is described in UniProt as null. Variant chr11-33710247-C-T is described in UniProt as null. Variant chr11-33710247-C-T is described in UniProt as null. Variant chr11-33710247-C-T is described in UniProt as null. Variant chr11-33710247-C-T is described in UniProt as null. Variant chr11-33710247-C-T is described in UniProt as null. Variant chr11-33710247-C-T is described in UniProt as null. Variant chr11-33710247-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD59	NM_000611.6	c.266G>A	p.Cys89Tyr	missense_variant	4/4	ENST00000642928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD59	ENST00000642928.2	c.266G>A	p.Cys89Tyr	missense_variant	4/4		NM_000611.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251404 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135880

Gnomad AFR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary CD59 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 03, 2013

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 15, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CD59 function (PMID: 23149847). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 64690). This missense change has been observed in individuals with CD59 deficiency (PMID: 23149847). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs397514767, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 89 of the CD59 protein (p.Cys89Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;.;.;.;.;.;.;.;.;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.7	D;.;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0040	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		0.79
MutPred		0.89		Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);Loss of methylation at K90 (P = 0.0177);
MVP		1.0
MPC		0.90
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs397514767; hg19: chr11-33731793;