20-23825296-C-T

Variant names:

• chr20-23825296-C-T
• rs371142839
• NM_001322.3:c.256G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001322.3(CST2):​c.256G>A​(p.Asp86Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000050 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CST2 NM_001322.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.874
• Publications: 0 publications found

Genes affected

CST2 (HGNC:2474): (cystatin SA) 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 a secreted thiol protease inhibitor found at high levels in saliva, tears and seminal plasma. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20848158).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322.3. 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
	CST2	NM_001322.3	MANE Select	c.256G>A	p.Asp86Asn	missense	Exon 2 of 3	NP_001313.1	P09228

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST2	ENST00000304725.3	TSL:1 MANE Select	c.256G>A	p.Asp86Asn	missense	Exon 2 of 3	ENSP00000307540.2	P09228

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 12 AN: 112800 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000962

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: 0.0000768

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000283 AC: 7 AN: 247410 AF XY: 0.0000299

Gnomad AFR exome AF: 0.0000633

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: 0.0000533

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000503 AC: 69 AN: 1373124 Hom.: 0 Cov.: 36 AF XY: 0.0000515 AC XY: 35 AN XY: 679636

African (AFR) AF: 0.000130 AC: 4 AN: 30686

American (AMR) AF: 0.00 AC: 0 AN: 40108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24208

East Asian (EAS) AF: 0.00 AC: 0 AN: 35296

South Asian (SAS) AF: 0.00 AC: 0 AN: 69348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5476

European-Non Finnish (NFE) AF: 0.0000565 AC: 60 AN: 1062324

Other (OTH) AF: 0.0000894 AC: 5 AN: 55940

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000106 AC: 12 AN: 112800 Hom.: 0 Cov.: 30 AF XY: 0.000127 AC XY: 7 AN XY: 55040

African (AFR) AF: 0.000240 AC: 7 AN: 29194

American (AMR) AF: 0.0000962 AC: 1 AN: 10392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3948

South Asian (SAS) AF: 0.00 AC: 0 AN: 3726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 184

European-Non Finnish (NFE) AF: 0.0000768 AC: 4 AN: 52094

Other (OTH) AF: 0.00 AC: 0 AN: 1412

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.00097	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.87
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.023
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		0.84	P
Vest4		0.19
MVP		0.26
MPC		0.0060
ClinPred		0.28	T
GERP RS		1.3
Varity_R		0.053
gMVP		0.17
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371142839; hg19: chr20-23805933;