rs2070856

Variant names:

• chr20-23750775-G-A
• rs2070856
• NM_001898.3:c.92C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-23750775-G-A
• chr20-23750775-G-T

Variant summary

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

The NM_001898.3(CST1):​c.92C>T​(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,842 control chromosomes in the GnomAD database, including 19,097 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.

• Frequency:
  • Genomes: 𝑓 0.15 (2045 hom., cov: 31)
  • Exomes 𝑓: 0.14 (17052 hom.)
• Consequence: CST1 NM_001898.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 21 publications found

Genes affected

CST1 (HGNC:2473): (cystatin SN) 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 cysteine proteinase inhibitor found in saliva, tears, urine, and seminal fluid. [provided by RefSeq, Jul 2008]

CST1 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: LIMITED Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.039392084).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST1	NM_001898.3	c.92C>T	p.Pro31Leu	missense_variant	Exon 1 of 3	ENST00000304749.7	NP_001889.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CST1	ENST00000304749.7	c.92C>T	p.Pro31Leu	missense_variant	Exon 1 of 3	1	NM_001898.3	ENSP00000305731.2
CST1	ENST00000398402.1	c.92C>T	p.Pro31Leu	missense_variant	Exon 2 of 4	5		ENSP00000381439.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23516 AN: 152004 Hom.: 2041 Cov.: 31

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.0711

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.145 AC: 36354 AN: 251334 AF XY: 0.154

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0636

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.0752

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.144 AC: 211180 AN: 1461718 Hom.: 17052 Cov.: 33 AF XY: 0.149 AC XY: 108333 AN XY: 727172

African (AFR) AF: 0.228 AC: 7626 AN: 33480

American (AMR) AF: 0.0660 AC: 2950 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 3072 AN: 26134

East Asian (EAS) AF: 0.0751 AC: 2982 AN: 39698

South Asian (SAS) AF: 0.303 AC: 26139 AN: 86250

European-Finnish (FIN) AF: 0.132 AC: 7068 AN: 53414

Middle Eastern (MID) AF: 0.115 AC: 662 AN: 5766

European-Non Finnish (NFE) AF: 0.137 AC: 152030 AN: 1111868

Other (OTH) AF: 0.143 AC: 8651 AN: 60392

GnomAD4 genome AF: 0.155 AC: 23538 AN: 152124 Hom.: 2045 Cov.: 31 AF XY: 0.156 AC XY: 11593 AN XY: 74364

African (AFR) AF: 0.216 AC: 8971 AN: 41498

American (AMR) AF: 0.0901 AC: 1378 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 381 AN: 3472

East Asian (EAS) AF: 0.0708 AC: 364 AN: 5138

South Asian (SAS) AF: 0.312 AC: 1501 AN: 4810

European-Finnish (FIN) AF: 0.137 AC: 1455 AN: 10610

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9071 AN: 67990

Other (OTH) AF: 0.122 AC: 257 AN: 2108

Alfa AF: 0.133 Hom.: 6060

Bravo AF: 0.148

TwinsUK AF: 0.135 AC: 499

ALSPAC AF: 0.146 AC: 563

ESP6500AA AF: 0.206 AC: 908

ESP6500EA AF: 0.135 AC: 1157

ExAC AF: 0.151 AC: 18376

Asia WGS AF: 0.237 AC: 824 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.126

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.061
DANN	Benign	0.51
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00030	N
LIST_S2	Benign	0.24	.;T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		-1.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.79	N;N
REVEL	Benign	0.034
Sift	Benign	0.34	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0030	B;B
Vest4		0.026
MPC		0.0034
ClinPred		0.0025	T
GERP RS		-2.9
PromoterAI		-0.00010	Neutral
Varity_R		0.035
gMVP		0.22
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs2070856; hg19: chr20-23731412; COSMIC: COSV104612812;