chr20-23637609-G-A

Variant names:

• chr20-23637609-G-A
• rs368971982
• NM_000099.4:c.243+11C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000099.4(CST3):​c.243+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,512,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CST3 NM_000099.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.554
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 20-23637609-G-A is Benign according to our data. Variant chr20-23637609-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1668603.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 15 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	NM_000099.4	MANE Select	c.243+11C>T		intron	N/A	NP_000090.1	P01034
	CST3	NM_001288614.2		c.243+11C>T		intron	N/A	NP_001275543.1	P01034

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	ENST00000376925.8	TSL:1 MANE Select	c.243+11C>T		intron	N/A	ENSP00000366124.3	P01034
	CST3	ENST00000398411.5	TSL:1	c.243+11C>T		intron	N/A	ENSP00000381448.1	P01034
	CST3	ENST00000398409.1	TSL:3	c.243+11C>T		intron	N/A	ENSP00000381446.1	P01034

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000169 AC: 2 AN: 118194 AF XY: 0.0000157

Gnomad AFR exome AF: 0.000282

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: 0.0000227

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 33 AN: 1360368 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 12 AN XY: 670242

African (AFR) AF: 0.000218 AC: 6 AN: 27556

American (AMR) AF: 0.00 AC: 0 AN: 31876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23846

East Asian (EAS) AF: 0.00 AC: 0 AN: 31414

South Asian (SAS) AF: 0.00 AC: 0 AN: 75410

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 47044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3960

European-Non Finnish (NFE) AF: 0.0000235 AC: 25 AN: 1063108

Other (OTH) AF: 0.0000178 AC: 1 AN: 56154

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74364

African (AFR) AF: 0.000338 AC: 14 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.1
DANN	Uncertain	0.98
PhyloP100		-0.55
PromoterAI		0.0034	Neutral

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: rs368971982; hg19: chr20-23618246;