Genetic Variant CAAP1:p.Ile357Val (chr9-26842318-T-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_024828.4(CAAP1):c.1069A>G(p.Ile357Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 1,570,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I357T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CAAP1
NM_024828.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.838

Publications

1 publications found

Variant links:

Genes affected

CAAP1 (HGNC:25834): (caspase activity and apoptosis inhibitor 1) Involved in negative regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway. [provided by Alliance of Genome Resources, Apr 2022]

CAAP1 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

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023937434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAAP1	NM_024828.4 link	c.1069A>G	p.Ile357Val	missense_variant	Exon 6 of 6	ENST00000333916.8	NP_079104.3	Q9H8G2-1
CAAP1	NM_001167575.2 link	c.634A>G	p.Ile212Val	missense_variant	Exon 6 of 6		NP_001161047.1	Q9H8G2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAAP1	ENST00000333916.8 link	c.1069A>G	p.Ile357Val	missense_variant	Exon 6 of 6	1	NM_024828.4	ENSP00000369431.3		Q9H8G2-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1417944

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

701340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31332

American (AMR)

AF:

0.00

AC:

AN:

35388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23874

East Asian (EAS)

AF:

0.00

AC:

AN:

39208

South Asian (SAS)

AF:

0.00

AC:

AN:

79620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5446

European-Non Finnish (NFE)

AF:

0.00000275

AC:

AN:

1092216

Other (OTH)

AF:

0.00

AC:

AN:

58326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1069A>G (p.I357V) alteration is located in exon 6 (coding exon 6) of the CAAP1 gene. This alteration results from a A to G substitution at nucleotide position 1069, causing the isoleucine (I) at amino acid position 357 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.9

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0028

T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.83

N;.

PhyloP100

0.84

PrimateAI

Benign

0.34

PROVEAN

Benign

0.11

N;.

REVEL

Benign

0.040

Sift

Benign

0.56

T;.

Sift4G

Benign

0.90

T;T

Polyphen

0.0

B;.

Vest4

0.026

MutPred

0.18

Gain of methylation at K358 (P = 0.0823);.;

MVP

0.17

MPC

0.11

ClinPred

0.050

GERP RS

3.7

Varity_R

0.022

gMVP

0.024

Mutation Taster

=86/14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over