20-23879541-A-G

Variant names:

• chr20-23879541-A-G
• rs1799841
• NM_001900.5:c.136T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001900.5(CST5):​c.136T>C​(p.Cys46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,613,572 control chromosomes in the GnomAD database, including 174,748 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. C46Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.54 (23272 hom., cov: 32)
  • Exomes 𝑓: 0.45 (151476 hom.)
• Consequence: CST5 NM_001900.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92
• Publications: 38 publications found

Genes affected

CST5 (HGNC:2477): (cystatin D) 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 protein found in saliva and tears. The encoded protein may play a protective role against proteinases present in the oral cavity. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0220704E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001900.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST5	NM_001900.5	MANE Select	c.136T>C	p.Cys46Arg	missense	Exon 1 of 3	NP_001891.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST5	ENST00000304710.5	TSL:1 MANE Select	c.136T>C	p.Cys46Arg	missense	Exon 1 of 3	ENSP00000307132.4

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81230 AN: 151762 Hom.: 23230 Cov.: 32

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.478

GnomAD2 exomes AF: 0.482 AC: 121082 AN: 251316 AF XY: 0.470

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.567

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.480

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.451 AC: 659059 AN: 1461694 Hom.: 151476 Cov.: 51 AF XY: 0.450 AC XY: 326915 AN XY: 727162

African (AFR) AF: 0.766 AC: 25630 AN: 33476

American (AMR) AF: 0.561 AC: 25098 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 9317 AN: 26128

East Asian (EAS) AF: 0.463 AC: 18398 AN: 39698

South Asian (SAS) AF: 0.448 AC: 38601 AN: 86252

European-Finnish (FIN) AF: 0.527 AC: 28144 AN: 53402

Middle Eastern (MID) AF: 0.360 AC: 2077 AN: 5766

European-Non Finnish (NFE) AF: 0.436 AC: 484262 AN: 1111864

Other (OTH) AF: 0.456 AC: 27532 AN: 60390

GnomAD4 genome AF: 0.535 AC: 81326 AN: 151878 Hom.: 23272 Cov.: 32 AF XY: 0.537 AC XY: 39829 AN XY: 74204

African (AFR) AF: 0.756 AC: 31320 AN: 41420

American (AMR) AF: 0.491 AC: 7495 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1234 AN: 3468

East Asian (EAS) AF: 0.482 AC: 2472 AN: 5124

South Asian (SAS) AF: 0.435 AC: 2086 AN: 4800

European-Finnish (FIN) AF: 0.550 AC: 5813 AN: 10570

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29407 AN: 67902

Other (OTH) AF: 0.474 AC: 999 AN: 2108

Alfa AF: 0.456 Hom.: 81610

Bravo AF: 0.546

TwinsUK AF: 0.439 AC: 1629

ALSPAC AF: 0.435 AC: 1676

ESP6500AA AF: 0.749 AC: 3301

ESP6500EA AF: 0.435 AC: 3740

ExAC AF: 0.483 AC: 58625

Asia WGS AF: 0.473 AC: 1647 AN: 3478

EpiCase AF: 0.413

EpiControl AF: 0.417

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.021
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.027
DANN	Benign	0.11
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00012	N
LIST_S2	Benign	0.039	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		-1.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	5.3	N
REVEL	Benign	0.016
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.0043
ClinPred		0.010	T
GERP RS		-0.40
PromoterAI		0.037	Neutral
Varity_R		0.10
gMVP		0.22
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1799841; hg19: chr20-23860178; COSMIC: COSV59013981;