16-546893-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_005632.3(CAPN15):​c.55G>A​(p.Gly19Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,611,540 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

CAPN15
NM_005632.3 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.01
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.104115814).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00019 (29/152354) while in subpopulation AFR AF= 0.000529 (22/41578). AF 95% confidence interval is 0.000358. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CAPN15NM_005632.3 linkuse as main transcriptc.55G>A p.Gly19Ser missense_variant 4/14 ENST00000219611.7 NP_005623.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CAPN15ENST00000219611.7 linkuse as main transcriptc.55G>A p.Gly19Ser missense_variant 4/141 NM_005632.3 ENSP00000219611 P1O75808-1
CAPN15ENST00000637507.1 linkuse as main transcriptc.259G>A p.Gly87Ser missense_variant 2/25 ENSP00000490480
CAPN15ENST00000562370.5 linkuse as main transcriptc.55G>A p.Gly19Ser missense_variant 3/32 ENSP00000456017
CAPN15ENST00000568988.5 linkuse as main transcriptc.-314-666G>A intron_variant 3 ENSP00000457030

Frequencies

GnomAD3 genomes
AF:
0.000190
AC:
29
AN:
152236
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.000955
GnomAD3 exomes
AF:
0.0000532
AC:
13
AN:
244498
Hom.:
0
AF XY:
0.0000299
AC XY:
4
AN XY:
133790
show subpopulations
Gnomad AFR exome
AF:
0.000587
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000377
AC:
55
AN:
1459186
Hom.:
1
Cov.:
32
AF XY:
0.0000317
AC XY:
23
AN XY:
725982
show subpopulations
Gnomad4 AFR exome
AF:
0.000896
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000176
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000195
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000190
AC:
29
AN:
152354
Hom.:
0
Cov.:
34
AF XY:
0.000148
AC XY:
11
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000529
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000201
Hom.:
0
Bravo
AF:
0.000272
ESP6500AA
AF:
0.000686
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000830
AC:
10

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 28, 2022The c.55G>A (p.G19S) alteration is located in exon 4 (coding exon 1) of the CAPN15 gene. This alteration results from a G to A substitution at nucleotide position 55, causing the glycine (G) at amino acid position 19 to be replaced by a serine (S). 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
0.083
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0068
T;T;T
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D;D;D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
.;L;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.85
N;N;.
REVEL
Benign
0.15
Sift
Benign
0.33
T;D;.
Sift4G
Uncertain
0.051
T;T;.
Polyphen
0.98
.;D;.
Vest4
0.65
MVP
0.45
ClinPred
0.12
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2071923; hg19: chr16-596893; API