Genetic Variant CLPSL1:p.Val75Leu (chr6-35787867-G-C) – 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_001010886.5(CLPSL1):c.223G>C(p.Val75Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. V75M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 41)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CLPSL1
NM_001010886.5 missense, splice_region

Scores

Splicing: ADA: 0.01153

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.489

Publications

1 publications found

Variant links:

Genes affected

CLPSL1 (HGNC:21251): (colipase like 1) Predicted to enable enzyme activator activity. Predicted to be involved in response to food. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

CLPSL1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03517714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CLPSL1	NM_001010886.5 link	c.223G>C	p.Val75Leu	missense_variant, splice_region_variant	Exon 3 of 3	ENST00000373861.6	NP_001010886.1
CLPSL1	XM_017010820.2 link	c.235G>C	p.Val79Leu	missense_variant, splice_region_variant	Exon 2 of 2		XP_016866309.1
CLPSL1	NM_001348773.2 link	c.222+747G>C		intron_variant	Intron 2 of 2		NP_001335702.1
CLPSL1	XM_017010821.2 link	c.234+747G>C		intron_variant	Intron 1 of 1		XP_016866310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPSL1	ENST00000373861.6 link	c.223G>C	p.Val75Leu	missense_variant, splice_region_variant	Exon 3 of 3	1	NM_001010886.5	ENSP00000362968.5		A2RUU4
CLPSL1	ENST00000428710.1 link	c.81+747G>C		intron_variant	Intron 1 of 1	3		ENSP00000396556.1		Q5T9G0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249246

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725304

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108710

Other (OTH)

AF:

0.00

AC:

AN:

60248

⚠️ 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: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.5

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.010

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.18

M_CAP

Benign

0.0015

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.49

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.58

REVEL

Benign

0.020

Sift

Benign

0.16

Sift4G

Benign

0.28

Polyphen

0.0050

Vest4

0.042

MutPred

0.48

Loss of sheet (P = 0.0126);

MVP

0.072

MPC

0.021

ClinPred

0.018

GERP RS

0.0085

Varity_R

0.052

gMVP

0.33

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.54

Position offset: 0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over