dbSNP rs41270082: CLPS:p.Arg109Cys (chr6-35795160-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001832.4(CLPS):c.325C>T(p.Arg109Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00912 in 1,608,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0069 ( 0 hom., cov: 40)

Exomes 𝑓: 0.0094 ( 0 hom. )

Consequence

CLPS
NM_001832.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00100

Publications

12 publications found

Variant links:

Genes affected

CLPS (HGNC:2085): (colipase) The protein encoded by this gene is a cofactor needed by pancreatic lipase for efficient dietary lipid hydrolysis. It binds to the C-terminal, non-catalytic domain of lipase, thereby stabilizing an active conformation and considerably increasing the overall hydrophobic binding site. The gene product allows lipase to anchor noncovalently to the surface of lipid micelles, counteracting the destabilizing influence of intestinal bile salts. This cofactor is only expressed in pancreatic acinar cells, suggesting regulation of expression by tissue-specific elements. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

CLPS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Variant has high frequency in the NFE (0.0101) population. However there is too low homozygotes in high coverage region: (expected more than 33, got 0).

BP4

Computational evidence support a benign effect (MetaRNN=0.006454587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPS	NM_001832.4 link	c.325C>T	p.Arg109Cys	missense_variant	Exon 3 of 3	ENST00000259938.7	NP_001823.1	P04118
CLPS	NM_001252597.2 link	c.283C>T	p.Arg95Cys	missense_variant	Exon 4 of 4		NP_001239526.1	A0A087WZW1
CLPS	NM_001252598.2 link	c.202C>T	p.Arg68Cys	missense_variant	Exon 2 of 2		NP_001239527.1	A0A087X0Q7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLPS	ENST00000259938.7 link	c.325C>T	p.Arg109Cys	missense_variant	Exon 3 of 3	1	NM_001832.4	ENSP00000259938.2	P04118
CLPS	ENST00000616014.3 link	c.202C>T	p.Arg68Cys	missense_variant	Exon 2 of 2	1		ENSP00000483589.1	A0A087X0Q7
CLPS	ENST00000622413.2 link	c.283C>T	p.Arg95Cys	missense_variant	Exon 3 of 3	5		ENSP00000482919.1	A0A087WZW1

Frequencies

GnomAD3 genomes

AF:

0.00688

AC:

1046

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.0160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00851

AC:

2132

AN:

250422

AF XY:

0.00874

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0166

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.00802

GnomAD4 exome

AF:

0.00935

AC:

13623

AN:

1456370

Hom.:

Cov.:

AF XY:

0.00940

AC XY:

6808

AN XY:

724452

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00108

AC:

AN:

33466

American (AMR)

AF:

0.00210

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26106

East Asian (EAS)

AF:

0.000151

AC:

AN:

39696

South Asian (SAS)

AF:

0.00819

AC:

705

AN:

86044

European-Finnish (FIN)

AF:

0.0191

AC:

1016

AN:

53172

Middle Eastern (MID)

AF:

0.00371

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.0102

AC:

11315

AN:

1107318

Other (OTH)

AF:

0.00709

AC:

427

AN:

60210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

932

1864

2796

3728

4660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

388

776

1164

1552

1940

<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:

0.00689

AC:

1047

AN:

152062

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

526

AN XY:

74332

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00125

AC:

AN:

41576

American (AMR)

AF:

0.00144

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00746

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0160

AC:

169

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0112

AC:

758

AN:

67834

Other (OTH)

AF:

0.00426

AC:

AN:

2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.312

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.0104

Hom.:

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0110

AC:

ExAC

AF:

0.0115

AC:

1398

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.00989

EpiControl

AF:

0.0108

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;D;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.76

T;T;T

MetaRNN

Benign

0.0065

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

.;M;.

PhyloP100

-0.0010

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.0

.;D;.

REVEL

Benign

0.027

Sift

Uncertain

0.0030

.;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.0010

.;B;.

Vest4

0.13

MPC

1.1

ClinPred

0.042

GERP RS

-0.61

Varity_R

0.12

gMVP

0.79

Mutation Taster

=98/2

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over