Genetic Variant CAPN15:p.Arg52Leu (chr16-546993-G-T) – 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.155G>T(p.Arg52Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,744 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R52C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CAPN15
NM_005632.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.46

Publications

4 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.155G>T	p.Arg52Leu	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.155G>T	p.Arg52Leu	missense_variant	Exon 4 of 14	1	NM_005632.3	ENSP00000219611.2		O75808-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

245334

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457744

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111814

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.155G>T (p.R52L) alteration is located in exon 4 (coding exon 1) of the CAPN15 gene. This alteration results from a G to T substitution at nucleotide position 155, causing the arginine (R) at amino acid position 52 to be replaced by a leucine (L). 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

T;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.1

.;M;.

PhyloP100

9.5

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.9

D;D;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.0050

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;.

Vest4

0.80

MutPred

0.55

Loss of methylation at K47 (P = 0.052);Loss of methylation at K47 (P = 0.052);.;

MVP

0.19

ClinPred

0.88

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.64

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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16-546993-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over