11-77084916-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004055.5(CAPN5):c.30C>G(p.Asp10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,614,030 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D10G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (177 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (156 hom.)
• Consequence: CAPN5 NM_004055.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.182

Genes affected

CAPN5 (HGNC:1482): (calpain 5) Calpains are calcium-dependent cysteine proteases involved in signal transduction in a variety of cellular processes. A functional calpain protein consists of an invariant small subunit and 1 of a family of large subunits. CAPN5 is one of the large subunits. Unlike some of the calpains, CAPN5 and CAPN6 lack a calmodulin-like domain IV. Because of the significant similarity to Caenorhabditis elegans sex determination gene tra-3, CAPN5 is also called as HTRA3. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016339123).
• BP6: Variant 11-77084916-C-G is Benign according to our data. Variant chr11-77084916-C-G is described in ClinVar as [Benign]. Clinvar id is 259224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN5	NM_004055.5	c.30C>G	p.Asp10Glu	missense_variant	2/13	ENST00000648180.1
CAPN5	XM_011545225.1	c.150C>G	p.Asp50Glu	missense_variant	3/14
CAPN5	XM_017018223.3	c.138C>G	p.Asp46Glu	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN5	ENST00000648180.1	c.30C>G	p.Asp10Glu	missense_variant	2/13		NM_004055.5	P1

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3816 AN: 152162 Hom.: 175 Cov.: 33

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00889

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: 0.000191

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.00624 AC: 1568 AN: 251194 Hom.: 63 AF XY: 0.00455 AC XY: 618 AN XY: 135872

Gnomad AFR exome AF: 0.0866

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00266 AC: 3889 AN: 1461750 Hom.: 156 Cov.: 33 AF XY: 0.00225 AC XY: 1635 AN XY: 727180

Gnomad4 AFR exome AF: 0.0953

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.0251 AC: 3825 AN: 152280 Hom.: 177 Cov.: 33 AF XY: 0.0244 AC XY: 1816 AN XY: 74464

Gnomad4 AFR AF: 0.0877

Gnomad4 AMR AF: 0.00888

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00238 Hom.: 2

Bravo AF: 0.0287

ESP6500AA AF: 0.0918 AC: 404

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00783 AC: 950

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.066	T;T;T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.68	D
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;L;L;.
MutationTaster	Benign	0.63	D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;.;N;N
REVEL	Benign	0.034
Sift	Benign	0.071	T;T;.;T;T
Sift4G	Benign	0.29	T;T;.;T;T
Polyphen		0.0	B;.;B;B;B
Vest4		0.15
MutPred		0.37		Gain of ubiquitination at K6 (P = 0.07);Gain of ubiquitination at K6 (P = 0.07);Gain of ubiquitination at K6 (P = 0.07);Gain of ubiquitination at K6 (P = 0.07);Gain of ubiquitination at K6 (P = 0.07);
MVP		0.44
MPC		0.14
ClinPred		0.013	T
GERP RS		3.3
Varity_R		0.082
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

Other links and lift over

dbSNP: rs34801837; hg19: chr11-76795962;