dbSNP rs1445955153: CAPN15:p.Ala77Asp (chr16-547068-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005632.3(CAPN15):c.230C>A(p.Ala77Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,350 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. 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. A77V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CAPN15
NM_005632.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.86

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.089398146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN15	NM_005632.3 link	c.230C>A	p.Ala77Asp	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.230C>A	p.Ala77Asp	missense_variant	Exon 4 of 14	1	NM_005632.3	ENSP00000219611.2		O75808-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447350

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719542

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:

33312

American (AMR)

AF:

0.00

AC:

AN:

43864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25622

East Asian (EAS)

AF:

0.00

AC:

AN:

39224

South Asian (SAS)

AF:

0.00

AC:

AN:

84946

European-Finnish (FIN)

AF:

0.0000210

AC:

AN:

47620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107230

Other (OTH)

AF:

0.00

AC:

AN:

59806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.0029

BayesDel_noAF

Benign

-0.24

CADD

Benign

7.2

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.021

T;T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.81

T;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.089

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.5

.;L;.

PhyloP100

1.9

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

N;N;.

REVEL

Benign

0.20

Sift

Benign

0.061

T;T;.

Sift4G

Uncertain

0.017

D;T;.

Polyphen

0.36

.;B;.

Vest4

0.26

MutPred

0.24

Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);.;

MVP

0.10

ClinPred

0.18

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.066

gMVP

0.36

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over