chr20-23637934-T-G

Variant names:

• chr20-23637934-T-G
• rs73318135
• NM_000099.4:c.-72A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000099.4(CST3):​c.-72A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,270,140 control chromosomes in the GnomAD database, including 31,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3304 hom., cov: 31)
  • Exomes 𝑓: 0.23 (27844 hom.)
• Consequence: CST3 NM_000099.4 5_prime_UTR
• Scores: Splicing: ADA: 0.00001103
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.54
• Publications: 14 publications found

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]

CST3 Gene-Disease associations (from GenCC):

• ACys amyloidosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000286117 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-23637934-T-G is Benign according to our data. Variant chr20-23637934-T-G is described in ClinVar as Benign. ClinVar VariationId is 402569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000099.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	NM_000099.4	MANE Select	c.-72A>C		5_prime_UTR	Exon 1 of 3	NP_000090.1
	CST3	NM_001288614.2		c.-72A>C		5_prime_UTR	Exon 1 of 4	NP_001275543.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	ENST00000376925.8	TSL:1 MANE Select	c.-72A>C		5_prime_UTR	Exon 1 of 3	ENSP00000366124.3
	CST3	ENST00000398411.5	TSL:1	c.-72A>C		5_prime_UTR	Exon 1 of 4	ENSP00000381448.1
	CST3	ENST00000398409.1	TSL:3	c.-70-2A>C		splice_acceptor intron	N/A	ENSP00000381446.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 30722 AN: 150196 Hom.: 3306 Cov.: 31

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.227 AC: 253908 AN: 1119832 Hom.: 27844 Cov.: 31 AF XY: 0.229 AC XY: 123478 AN XY: 539788

African (AFR) AF: 0.241 AC: 5123 AN: 21238

American (AMR) AF: 0.152 AC: 1051 AN: 6916

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 2653 AN: 13154

East Asian (EAS) AF: 0.175 AC: 3427 AN: 19558

South Asian (SAS) AF: 0.312 AC: 13868 AN: 44456

European-Finnish (FIN) AF: 0.283 AC: 6264 AN: 22150

Middle Eastern (MID) AF: 0.169 AC: 486 AN: 2874

European-Non Finnish (NFE) AF: 0.223 AC: 211166 AN: 945926

Other (OTH) AF: 0.227 AC: 9870 AN: 43560

GnomAD4 genome AF: 0.204 AC: 30723 AN: 150308 Hom.: 3304 Cov.: 31 AF XY: 0.205 AC XY: 15070 AN XY: 73402

African (AFR) AF: 0.215 AC: 8857 AN: 41252

American (AMR) AF: 0.133 AC: 2014 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 563 AN: 3460

East Asian (EAS) AF: 0.140 AC: 606 AN: 4332

South Asian (SAS) AF: 0.324 AC: 1517 AN: 4686

European-Finnish (FIN) AF: 0.231 AC: 2394 AN: 10364

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.210 AC: 14248 AN: 67724

Other (OTH) AF: 0.189 AC: 397 AN: 2102

Alfa AF: 0.168 Hom.: 886

Bravo AF: 0.190

Asia WGS AF: 0.183 AC: 633 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 410/2178=18.8%

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.0
DANN	Benign	0.41
PhyloP100		-3.5
PromoterAI		0.016	Neutral
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
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: rs73318135; hg19: chr20-23618571;