rs371142839

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-23825296-C-A
• chr20-23825296-C-G
• chr20-23825296-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001322.3(CST2):​c.256G>T​(p.Asp86Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000606 in 1,486,066 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D86N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: CST2 NM_001322.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Asp86Tyr	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>T	p.Asp86Tyr	missense	Exon 2 of 3	ENSP00000307540.2	P09228

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112888 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000684

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: 0.00

GnomAD4 exome AF: 0.00000510 AC: 7 AN: 1373178 Hom.: 0 Cov.: 36 AF XY: 0.00000294 AC XY: 2 AN XY: 679660

African (AFR) AF: 0.00 AC: 0 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: 0.000113 AC: 4 AN: 35300

South Asian (SAS) AF: 0.00 AC: 0 AN: 69356

European-Finnish (FIN) AF: 0.0000402 AC: 2 AN: 49740

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062360

Other (OTH) AF: 0.0000179 AC: 1 AN: 55944

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112888 Hom.: 0 Cov.: 30 AF XY: 0.0000182 AC XY: 1 AN XY: 55094

African (AFR) AF: 0.0000684 AC: 2 AN: 29238

American (AMR) AF: 0.00 AC: 0 AN: 10400

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: 3730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8520

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52110

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.00090	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-0.87
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.041
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.56		Loss of catalytic residue at D86 (P = 0.0941)
MVP		0.39
MPC		0.0095
ClinPred		0.85	D
GERP RS		1.3
Varity_R		0.23
gMVP		0.33
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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;