NM_001322.3:c.248A>C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• 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_pathogenic. The variant received 6 ACMG points.

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

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.248A>C	p.Tyr83Ser	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.248A>C	p.Tyr83Ser	missense	Exon 2 of 3	ENSP00000307540.2	P09228

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 28

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	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
PhyloP100		0.76
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
Mutation Taster		=94/6	polymorphism

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

hg19: chr20-23805941;