16-547112-G-A

Position:

chr16-547112-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_005632.3(CAPN15):c.274G>A(p.Ala92Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,574,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

CAPN15
NM_005632.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.327

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.003355682).

BP6

Variant 16-547112-G-A is Benign according to our data. Variant chr16-547112-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2254835.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000263 (40/152344) while in subpopulation AMR AF= 0.000457 (7/15314). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN15	NM_005632.3 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	4/14	ENST00000219611.7	NP_005623.1	O75808-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CAPN15	ENST00000219611.7 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	4/14	1	NM_005632.3	ENSP00000219611.2	O75808-1
CAPN15	ENST00000637507.1 linkuse as main transcript	c.478G>A	p.Ala160Thr	missense_variant	2/2	5		ENSP00000490480.1	A0A1B0GVE3
CAPN15	ENST00000562370.5 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	3/3	2		ENSP00000456017.1	H3BR03
CAPN15	ENST00000568988.5 linkuse as main transcript	c.-314-447G>A		intron_variant		3		ENSP00000457030.1	H3BT55

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000621

AC:

122

AN:

196604

Hom.:

AF XY:

0.000630

AC XY:

AN XY:

107968

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000485

Gnomad ASJ exome

AF:

0.00688

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000162

Gnomad FIN exome

AF:

0.000150

Gnomad NFE exome

AF:

0.000471

Gnomad OTH exome

AF:

0.00203

GnomAD4 exome

AF:

0.000320

AC:

455

AN:

1422490

Hom.:

Cov.:

AF XY:

0.000335

AC XY:

236

AN XY:

704354

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000501

Gnomad4 ASJ exome

AF:

0.00571

Gnomad4 EAS exome

AF:

0.0000258

Gnomad4 SAS exome

AF:

0.000172

Gnomad4 FIN exome

AF:

0.0000668

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.000263

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00151

Hom.:

Bravo

AF:

0.000412

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000452

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CAPN15-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.060

DANN

Benign

0.53

DEOGEN2

Benign

0.0034

T;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.60

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.34

.;N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.21

N;N;.

REVEL

Benign

0.23

Sift

Benign

0.83

T;T;.

Sift4G

Benign

0.68

T;T;.

Polyphen

0.0020

.;B;.

Vest4

0.050

MVP

0.48

ClinPred

0.0094

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.012

gMVP

0.14

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over