20-23688851-T-C

Variant names:

• chr20-23688851-T-C
• rs73902130
• NM_001899.3:c.119A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001899.3(CST4):​c.119A>G​(p.Asn40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 1,614,134 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (193 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (172 hom.)
• Consequence: CST4 NM_001899.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.375

Genes affected

CST4 (HGNC:2476): (cystatin S) 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. 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 type 2 salivary cysteine peptidase inhibitor. The protein is an S-type cystatin, based on its high level of expression in saliva, tears and seminal plasma. The specific role in these fluids is unclear but antibacterial and antiviral activity is present, consistent with a protective function. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039435327).
• BP6: Variant 20-23688851-T-C is Benign according to our data. Variant chr20-23688851-T-C is described in ClinVar as [Benign]. Clinvar id is 769081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST4	NM_001899.3	c.119A>G	p.Asn40Ser	missense_variant	Exon 1 of 3	ENST00000217423.4	NP_001890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CST4	ENST00000217423.4	c.119A>G	p.Asn40Ser	missense_variant	Exon 1 of 3	1	NM_001899.3	ENSP00000217423.3

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4247 AN: 152132 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00725 AC: 1824 AN: 251488 Hom.: 81 AF XY: 0.00499 AC XY: 678 AN XY: 135916

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00413

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00277 AC: 4047 AN: 1461884 Hom.: 172 Cov.: 32 AF XY: 0.00233 AC XY: 1693 AN XY: 727246

Gnomad4 AFR exome AF: 0.0992

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.0279 AC: 4245 AN: 152250 Hom.: 193 Cov.: 32 AF XY: 0.0265 AC XY: 1969 AN XY: 74440

Gnomad4 AFR AF: 0.0972

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00506 Hom.: 40

Bravo AF: 0.0312

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0928 AC: 409

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00882 AC: 1071

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.55
DEOGEN2	Benign	0.056	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.36	N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.044
Sift	Benign	0.18	T
Sift4G	Benign	0.42	T
Polyphen		0.0030	B
Vest4		0.11
MVP		0.21
MPC		0.0046
ClinPred		0.0017	T
GERP RS		1.0
Varity_R		0.080
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs73902130; hg19: chr20-23669488;