20-23825304-T-G

Variant names:

• chr20-23825304-T-G
• NM_001322.3:c.248A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001322.3(CST2):​c.248A>C​(p.Tyr83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: CST2 NM_001322.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.756

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST2	NM_001322.3	c.248A>C	p.Tyr83Ser	missense_variant	Exon 2 of 3	ENST00000304725.3	NP_001313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CST2	ENST00000304725.3	c.248A>C	p.Tyr83Ser	missense_variant	Exon 2 of 3	1	NM_001322.3	ENSP00000307540.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.248A>C (p.Y83S) alteration is located in exon 2 (coding exon 2) of the CST2 gene. This alteration results from a A to C substitution at nucleotide position 248, causing the tyrosine (Y) at amino acid position 83 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0013	T
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.85		Loss of stability (P = 0.0478);
MVP		0.53
MPC		0.0084
ClinPred		0.94	D
GERP RS		1.1
Varity_R		0.84
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-23805941;