Variant 6-44172362-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007058.4(CAPN11):c.470G>A(p.Arg157His) variant causes a missense change. The variant allele was found at a frequency of 0.000176 in 1,562,210 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 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

CAPN11
NM_007058.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.87

Variant links:

Genes affected

CAPN11 (HGNC:1478): (calpain 11) Calpains constitute a family of intracellular calcium-dependent cysteine proteases. There are eight members in this superfamily. They consist of a variable 80 kDa subunit and an invariant 30 kDa subunit. This calpain protein appears to have protease activity and calcium-binding ability. A similar mouse protein may play a functional role in spermatogenesis and in the regulation of calcium-dependent signal transduction events during meiosis. [provided by RefSeq, Dec 2008]

CAPN11 links:

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

POLR1C links:

CAPN11 (HGNC:):

CAPN11 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29490656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN11	NM_007058.4 linkuse as main transcript	c.470G>A	p.Arg157His	missense_variant	5/23	ENST00000398776.2	NP_008989.2	Q9UMQ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN11	ENST00000398776.2 linkuse as main transcript	c.470G>A	p.Arg157His	missense_variant	5/23	1	NM_007058.4	ENSP00000381758.1		Q9UMQ6
CAPN11	ENST00000532171.5 linkuse as main transcript	c.*13G>A		downstream_gene_variant		4		ENSP00000432420.1		E9PQZ4

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000384

AC:

AN:

171958

Hom.:

AF XY:

0.000504

AC XY:

AN XY:

91246

show subpopulations

Gnomad AFR exome

AF:

0.000778

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00228

Gnomad FIN exome

AF:

0.000172

Gnomad NFE exome

AF:

0.0000283

Gnomad OTH exome

AF:

0.000213

GnomAD4 exome

AF:

0.000167

AC:

236

AN:

1409972

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

159

AN XY:

696520

show subpopulations

Gnomad4 AFR exome

AF:

0.000751

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00210

Gnomad4 FIN exome

AF:

0.000241

Gnomad4 NFE exome

AF:

0.0000203

Gnomad4 OTH exome

AF:

0.000171

GnomAD4 genome

AF:

0.000256

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000517

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000225

AC:

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 submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.470G>A (p.R157H) alteration is located in exon 5 (coding exon 5) of the CAPN11 gene. This alteration results from a G to A substitution at nucleotide position 470, causing the arginine (R) at amino acid position 157 to be replaced by a histidine (H). 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

0.15

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.024

MetaRNN

Benign

0.29

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.2

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.78

MVP

0.95

MPC

0.51

ClinPred

0.23

GERP RS

4.0

Varity_R

0.80

gMVP

0.69

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