20-23637790-C-T

Position:

• chr20-23637790-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000099.4(CST3):​c.73G>A​(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,523,760 control chromosomes in the GnomAD database, including 35,388 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3317 hom., cov: 33)
  • Exomes 𝑓: 0.21 (32071 hom.)
• Consequence: CST3 NM_000099.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: -0.602

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 Benign. Variant got -18 ACMG points.

• PM1: In a mutagenesis_site Shows a dual distribution to the Golgi apparatus and to the mitochondria. (size 0) in uniprot entity CYTC_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043253005).
• BP6: Variant 20-23637790-C-T is Benign according to our data. Variant chr20-23637790-C-T is described in ClinVar as [Benign]. Clinvar id is 5635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-23637790-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CST3	NM_000099.4	c.73G>A	p.Ala25Thr	missense_variant	1/3	ENST00000376925.8	NP_000090.1
CST3	NM_001288614.2	c.73G>A	p.Ala25Thr	missense_variant	1/4		NP_001275543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CST3	ENST00000376925.8	c.73G>A	p.Ala25Thr	missense_variant	1/3	1	NM_000099.4	ENSP00000366124.3
CST3	ENST00000398411.5	c.73G>A	p.Ala25Thr	missense_variant	1/4	1		ENSP00000381448.1
CST3	ENST00000398409.1	c.73G>A	p.Ala25Thr	missense_variant	2/4	3		ENSP00000381446.1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30788 AN: 152002 Hom.: 3319 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.154

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.190

GnomAD3 exomes AF: 0.202 AC: 24976 AN: 123942 Hom.: 2800 AF XY: 0.212 AC XY: 14187 AN XY: 67052

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0941

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.297

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.213 AC: 292258 AN: 1371652 Hom.: 32071 Cov.: 44 AF XY: 0.216 AC XY: 145909 AN XY: 676174

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.0995

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.222

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.202 AC: 30789 AN: 152108 Hom.: 3317 Cov.: 33 AF XY: 0.203 AC XY: 15117 AN XY: 74374

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.188

Alfa AF: 0.196 Hom.: 1036

Bravo AF: 0.190

TwinsUK AF: 0.210 AC: 777

ALSPAC AF: 0.221 AC: 853

ESP6500AA AF: 0.184 AC: 727

ESP6500EA AF: 0.175 AC: 1322

ExAC AF: 0.120 AC: 9151

Asia WGS AF: 0.184 AC: 637 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Age related macular degeneration 11 Pathogenic:1 Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000099.2:c.73G>A in the gene CST3 has an allele frequency of 0.297 in South Asian subpopulation in the gnomAD database. A total of 3515 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1; BS2. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.229, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Hereditary cerebral amyloid angiopathy, Icelandic type;C2677774:Age related macular degeneration 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.87
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.33	.;.;T
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.094	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.019
MPC		0.42
ClinPred		0.00054	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.58

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: rs1064039; hg19: chr20-23618427; COSMIC: COSV65361855;