11-77084907-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_004055.5(CAPN5):c.21C>G(p.Pro7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,966 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CAPN5 NM_004055.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.07

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 11-77084907-C-G is Benign according to our data. Variant chr11-77084907-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1168849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77084907-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BS2: High AC in GnomAd at 107 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN5	NM_004055.5	c.21C>G	p.Pro7=	synonymous_variant	2/13	ENST00000648180.1
CAPN5	XM_011545225.1	c.141C>G	p.Pro47=	synonymous_variant	3/14
CAPN5	XM_017018223.3	c.129C>G	p.Pro43=	synonymous_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN5	ENST00000648180.1	c.21C>G	p.Pro7=	synonymous_variant	2/13		NM_004055.5	P1

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.00123

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000561 AC: 141 AN: 251214 Hom.: 0 AF XY: 0.000523 AC XY: 71 AN XY: 135884

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00131 AC: 1908 AN: 1461774 Hom.: 2 Cov.: 33 AF XY: 0.00121 AC XY: 879 AN XY: 727190

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74354

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000995 Hom.: 0

Bravo AF: 0.000895

EpiCase AF: 0.00142

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

CAPN5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2020

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
BayesDel_noAF	Benign	-0.39
Cadd	Benign	8.6
Dann	Benign	0.65

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: rs141606826; hg19: chr11-76795953;