11-33710247-C-T

Variant names:

• chr11-33710247-C-T
• rs397514767
• NM_000611.6:c.266G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 22 publications found

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

ENSG00000284969 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Pathogenic. Clinvar id is 64690.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD59	NM_000611.6	c.266G>A	p.Cys89Tyr	missense_variant	Exon 4 of 4	ENST00000642928.2	NP_000602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD59	ENST00000642928.2	c.266G>A	p.Cys89Tyr	missense_variant	Exon 4 of 4		NM_000611.6	ENSP00000494884.1
ENSG00000284969	ENST00000534312.5	c.266G>A	p.Cys89Tyr	missense_variant	Exon 3 of 4	3		ENSP00000432362.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251404 AF XY: 0.00000736

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

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

Jan 03, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs397514767, gnomAD 0.0009%). 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. ClinVar contains an entry for this variant (Variation ID: 64690). 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. Experimental studies have shown that this missense change affects CD59 function (PMID: 23149847). For these reasons, this variant has been classified as Pathogenic. -

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
DEOGEN2	Pathogenic	0.90	.;D;D;D;D;D;D;D;D;.
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
MutationAssessor	Uncertain	2.8	.;M;M;M;M;M;M;M;M;.
PhyloP100		2.9
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514767; hg19: chr11-33731793;