Genetic Variant CAPN15:p.Pro81Arg (chr16-547080-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005632.3(CAPN15):c.242C>G(p.Pro81Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,596,532 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

CAPN15
NM_005632.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34

Publications

0 publications found

Variant links:

Genes affected

CAPN15 (HGNC:11182): (calpain 15) This gene encodes a protein containing zinc-finger-like repeats and a calpain-like protease domain. The encoded protein may function as a transcription factor, RNA-binding protein, or in protein-protein interactions during visual system development. [provided by RefSeq, Jul 2008]

CAPN15 Gene-Disease associations (from GenCC):

oculogastrointestinal-neurodevelopmental syndrome
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

CAPN15 links:

ENSG00000261691 (HGNC:58544):

ENSG00000261691 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN15	NM_005632.3 link	c.242C>G	p.Pro81Arg	missense_variant	Exon 4 of 14	ENST00000219611.7	NP_005623.1	O75808-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN15	ENST00000219611.7 link	c.242C>G	p.Pro81Arg	missense_variant	Exon 4 of 14	1	NM_005632.3	ENSP00000219611.2		O75808-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152256

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000182

AC:

AN:

220330

AF XY:

0.0000165

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:

0.0000407

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000360

AC:

AN:

1444276

Hom.:

Cov.:

AF XY:

0.0000320

AC XY:

AN XY:

717678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33258

American (AMR)

AF:

0.00

AC:

AN:

43614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25402

East Asian (EAS)

AF:

0.00

AC:

AN:

39200

South Asian (SAS)

AF:

0.00

AC:

AN:

84516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000434

AC:

AN:

1105258

Other (OTH)

AF:

0.0000669

AC:

AN:

59752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.242C>G (p.P81R) alteration is located in exon 4 (coding exon 1) of the CAPN15 gene. This alteration results from a C to G substitution at nucleotide position 242, causing the proline (P) at amino acid position 81 to be replaced by an arginine (R). 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

0.14

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.093

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Benign

1.9

.;L;.

PhyloP100

3.3

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.2

D;N;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0080

D;D;.

Sift4G

Uncertain

0.0060

D;T;.

Polyphen

0.98

.;D;.

Vest4

0.60

MVP

0.42

ClinPred

0.54

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.43

Mutation Taster

=88/12

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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chr16-547080-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over