20-23826524-C-T

Variant names:

• chr20-23826524-C-T
• rs144878011
• NM_001322.3:c.137G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001322.3(CST2):​c.137G>A​(p.Arg46His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: CST2 NM_001322.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017456323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST2	NM_001322.3	c.137G>A	p.Arg46His	missense_variant	Exon 1 of 3	ENST00000304725.3	NP_001313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CST2	ENST00000304725.3	c.137G>A	p.Arg46His	missense_variant	Exon 1 of 3	1	NM_001322.3	ENSP00000307540.2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251452 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135898

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000999 AC: 146 AN: 1461850 Hom.: 1 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727232

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74436

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137G>A (p.R46H) alteration is located in exon 1 (coding exon 1) of the CST2 gene. This alteration results from a G to A substitution at nucleotide position 137, causing the arginine (R) at amino acid position 46 to be replaced by a histidine (H). 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	Benign	0.12
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.74
DANN	Benign	0.94
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00034	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.00091	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.018
Sift	Benign	0.057	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.17
MVP		0.13
MPC		0.0027
ClinPred		0.0079	T
GERP RS		-4.1
Varity_R		0.038
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144878011; hg19: chr20-23807161; COSMIC: COSV59030455;