20-23635330-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000099.4(CST3):c.281T>A(p.Leu94Gln) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L94L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CST3 NM_000099.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.91

Genes affected

CST3 (HGNC:2475): (cystatin C) The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes the most abundant extracellular inhibitor of cysteine proteases, which is found in high concentrations in biological fluids and is expressed in virtually all organs of the body. A mutation in this gene has been associated with amyloid angiopathy. Expression of this protein in vascular wall smooth muscle cells is severely reduced in both atherosclerotic and aneurysmal aortic lesions, establishing its role in vascular disease. In addition, this protein has been shown to have an antimicrobial function, inhibiting the replication of herpes simplex virus. Alternative splicing results in multiple transcript variants encoding a single protein. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 20-23635330-A-T is Pathogenic according to our data. Variant chr20-23635330-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 5634.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-23635330-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CST3	NM_000099.4	c.281T>A	p.Leu94Gln	missense_variant	2/3	ENST00000376925.8
CST3	NM_001288614.2	c.281T>A	p.Leu94Gln	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CST3	ENST00000376925.8	c.281T>A	p.Leu94Gln	missense_variant	2/3	1	NM_000099.4	P1
CST3	ENST00000398411.5	c.281T>A	p.Leu94Gln	missense_variant	2/4	1		P1
CST3	ENST00000398409.1	c.281T>A	p.Leu94Gln	missense_variant	3/4	3		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary cerebral amyloid angiopathy, Icelandic type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 15, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Benign	0.092
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.23	N
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	4.3e-7	A;A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.87
MutPred		0.94		Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);
MVP		0.39
MPC		1.3
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.81

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: rs28939068; hg19: chr20-23615967;