20-23452606-C-G

Variant names:

• chr20-23452606-C-G
• rs140128807
• NM_130794.2:c.206G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_130794.2(CST11):​c.206G>C​(p.Arg69Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R69Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CST11 NM_130794.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 2 publications found

Genes affected

CST11 (HGNC:15959): (cystatin 11) 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 an epididymal-specific protein shown to have antimicrobial activity against E. coli. Alternative splicing yields two variants encoding distinct isoforms. [provided by RefSeq, Sep 2014]

CSTL1 (HGNC:15958): (cystatin like 1) 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 at the telomeric end of the cystatin locus and encodes a type 2 cystatin-like protein. The specific function of this protein has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000273838 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130794.2. 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
	CST11	NM_130794.2	MANE Select	c.206G>C	p.Arg69Pro	missense	Exon 1 of 3	NP_570612.1	A0A384P5Z6
	CST11	NM_080830.3		c.206G>C	p.Arg69Pro	missense	Exon 1 of 2	NP_543020.2
	CSTL1	NR_170939.1		n.372-456C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST11	ENST00000377009.8	TSL:1 MANE Select	c.206G>C	p.Arg69Pro	missense	Exon 1 of 3	ENSP00000366208.3	Q9H112-1
	CST11	ENST00000377007.3	TSL:1	c.206G>C	p.Arg69Pro	missense	Exon 1 of 2	ENSP00000366206.3	Q9H112-2
	CST11	ENST00000915941.1		c.206G>C	p.Arg69Pro	missense	Exon 2 of 4	ENSP00000586000.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251062 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460778 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111008

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0083	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.62		Loss of MoRF binding (P = 5e-04)
MVP		0.34
MPC		0.045
ClinPred		0.90	D
GERP RS		3.9
PromoterAI		-0.022	Neutral
Varity_R		0.94
gMVP		0.78
Mutation Taster		=87/13	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

dbSNP: rs140128807; hg19: chr20-23433243; COSMIC: COSV105286051; COSMIC: COSV105286051;