19-38731182-G-A

Position:

chr19-38731182-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_144691.4(CAPN12):c.1999C>T(p.Arg667Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,612,968 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 6 hom. )

Consequence

CAPN12
NM_144691.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.57

Variant links:

Genes affected

CAPN12 (HGNC:13249): (calpain 12) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes a member of the calpain large subunit family. [provided by RefSeq, Jun 2012]

CAPN12 links:

ACTN4 (HGNC:166): (actinin alpha 4) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

ACTN4 links:

CAPN12 (HGNC:):

CAPN12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010502547).

BP6

Variant 19-38731182-G-A is Benign according to our data. Variant chr19-38731182-G-A is described in ClinVar as [Benign]. Clinvar id is 3039932.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN12	NM_144691.4 linkuse as main transcript	c.1999C>T	p.Arg667Cys	missense_variant	19/21	ENST00000328867.9	NP_653292.2	Q6ZSI9
ACTN4	NM_004924.6 linkuse as main transcript	c.*1750G>A		3_prime_UTR_variant	21/21	ENST00000252699.7	NP_004915.2	O43707-1A0A0S2Z3G9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN12	ENST00000328867.9 linkuse as main transcript	c.1999C>T	p.Arg667Cys	missense_variant	19/21	1	NM_144691.4	ENSP00000331636.3		Q6ZSI9
ACTN4	ENST00000252699.7 linkuse as main transcript	c.*1750G>A		3_prime_UTR_variant	21/21	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

220

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00163

AC:

405

AN:

248874

Hom.:

AF XY:

0.00157

AC XY:

213

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00791

Gnomad EAS exome

AF:

0.000437

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00112

Gnomad NFE exome

AF:

0.00192

Gnomad OTH exome

AF:

0.00214

GnomAD4 exome

AF:

0.00172

AC:

2518

AN:

1460654

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1234

AN XY:

726608

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00689

Gnomad4 EAS exome

AF:

0.000327

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.00174

Gnomad4 NFE exome

AF:

0.00180

Gnomad4 OTH exome

AF:

0.00191

GnomAD4 genome

AF:

0.00144

AC:

220

AN:

152314

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00691

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00194

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.00131

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00231

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CAPN12-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as 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

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

.;.;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.80

T;.;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Pathogenic

3.1

.;.;M

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.9

.;.;D

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

.;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.53, 0.54

MVP

0.55

MPC

0.098

ClinPred

0.097

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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