dbSNP rs3746736: CSTL1:p.Trp88Arg (chr20-23443976-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_138283.1(CSTL1):c.262T>C(p.Trp88Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,612,164 control chromosomes in the GnomAD database, including 224,187 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.59 ( 28176 hom., cov: 33)

Exomes 𝑓: 0.51 ( 196011 hom. )

Consequence

CSTL1
NM_138283.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.270

Publications

42 publications found

Variant links:

Genes affected

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]

CSTL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=3.3079068E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138283.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSTL1	NM_138283.1	MANE Select	c.262T>C	p.Trp88Arg	missense	Exon 3 of 4	NP_612140.1	Q9H114
CSTL1	NR_170937.1		n.571T>C		non_coding_transcript_exon	Exon 4 of 5
CSTL1	NR_170938.1		n.646T>C		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTL1	ENST00000347397.5	TSL:1 MANE Select	c.262T>C	p.Trp88Arg	missense	Exon 3 of 4	ENSP00000344907.1	Q9H114
	CSTL1	ENST00000246020.3	TSL:1	c.262T>C	p.Trp88Arg	missense	Exon 3 of 4	ENSP00000246020.2	Q9H114

Frequencies

GnomAD3 genomes

AF:

0.592

AC:

89974

AN:

152004

Hom.:

28131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.800

Gnomad AMI

AF:

0.595

Gnomad AMR

AF:

0.577

Gnomad ASJ

AF:

0.552

Gnomad EAS

AF:

0.723

Gnomad SAS

AF:

0.536

Gnomad FIN

AF:

0.419

Gnomad MID

AF:

0.608

Gnomad NFE

AF:

0.491

Gnomad OTH

AF:

0.600

GnomAD2 exomes

AF:

0.544

AC:

136464

AN:

251004

AF XY:

0.537

show subpopulations

Gnomad AFR exome

AF:

0.804

Gnomad AMR exome

AF:

0.574

Gnomad ASJ exome

AF:

0.558

Gnomad EAS exome

AF:

0.722

Gnomad FIN exome

AF:

0.414

Gnomad NFE exome

AF:

0.497

Gnomad OTH exome

AF:

0.525

GnomAD4 exome

AF:

0.513

AC:

749646

AN:

1460042

Hom.:

196011

Cov.:

AF XY:

0.514

AC XY:

372979

AN XY:

726336

show subpopulations

African (AFR)

AF:

0.809

AC:

27067

AN:

33458

American (AMR)

AF:

0.576

AC:

25748

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.555

AC:

14490

AN:

26104

East Asian (EAS)

AF:

0.723

AC:

28691

AN:

39664

South Asian (SAS)

AF:

0.526

AC:

45294

AN:

86142

European-Finnish (FIN)

AF:

0.417

AC:

22269

AN:

53386

Middle Eastern (MID)

AF:

0.588

AC:

3387

AN:

5764

European-Non Finnish (NFE)

AF:

0.495

AC:

549914

AN:

1110492

Other (OTH)

AF:

0.543

AC:

32786

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

18199

36398

54598

72797

90996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16284

32568

48852

65136

81420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.592

AC:

90075

AN:

152122

Hom.:

28176

Cov.:

AF XY:

0.591

AC XY:

43939

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.800

AC:

33222

AN:

41518

American (AMR)

AF:

0.577

AC:

8820

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

1913

AN:

3468

East Asian (EAS)

AF:

0.723

AC:

3732

AN:

5164

South Asian (SAS)

AF:

0.537

AC:

2588

AN:

4820

European-Finnish (FIN)

AF:

0.419

AC:

4433

AN:

10568

Middle Eastern (MID)

AF:

0.616

AC:

181

AN:

294

European-Non Finnish (NFE)

AF:

0.491

AC:

33383

AN:

67986

Other (OTH)

AF:

0.598

AC:

1262

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1767

3534

5301

7068

8835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

726

1452

2178

2904

3630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.530

Hom.:

83083

Bravo

AF:

0.616

TwinsUK

AF:

0.494

AC:

1831

ALSPAC

AF:

0.483

AC:

1863

ESP6500AA

AF:

0.786

AC:

3464

ESP6500EA

AF:

0.504

AC:

4335

ExAC

AF:

0.546

AC:

66309

Asia WGS

AF:

0.607

AC:

2108

AN:

3478

EpiCase

AF:

0.504

EpiControl

AF:

0.505

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.40

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.014

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.089

MetaRNN

Benign

0.0000033

MetaSVM

Benign

-1.0

PhyloP100

-0.27

PrimateAI

Benign

0.38

PROVEAN

Benign

7.9

REVEL

Benign

0.086

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.17

MutPred

0.26

Gain of disorder (P = 0.0033)

MPC

0.093

ClinPred

0.0041

GERP RS

-0.60

Varity_R

0.068

gMVP

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over