11-77084938-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004055.5(CAPN5):c.52C>T(p.Arg18Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000203 in 1,613,774 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: CAPN5 NM_004055.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.35

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038357615).
• BP6: Variant 11-77084938-C-T is Benign according to our data. Variant chr11-77084938-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 501411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77084938-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN5	NM_004055.5	c.52C>T	p.Arg18Trp	missense_variant	2/13	ENST00000648180.1
CAPN5	XM_011545225.1	c.172C>T	p.Arg58Trp	missense_variant	3/14
CAPN5	XM_017018223.3	c.160C>T	p.Arg54Trp	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN5	ENST00000648180.1	c.52C>T	p.Arg18Trp	missense_variant	2/13		NM_004055.5	P1

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 250884 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135804

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000164 AC: 239 AN: 1461584 Hom.: 1 Cov.: 33 AF XY: 0.000169 AC XY: 123 AN XY: 727118

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000498 AC XY: 37 AN XY: 74328

Gnomad4 AFR AF: 0.00162

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000635

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 11, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;T;D;D;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.038	T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.2	D;D;.;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;.;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.49
MVP		0.61
MPC		0.63
ClinPred		0.099	T
GERP RS		3.1
Varity_R		0.33
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149132399; hg19: chr11-76795984; COSMIC: COSV53688969; COSMIC: COSV53688969;