11-65206824-G-A

Variant names:

• chr11-65206824-G-A
• rs375817528
• NM_005186.4:c.1605+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_005186.4(CAPN1):​c.1605+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,610,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CAPN1 NM_005186.4 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 1.26
• Publications: 5 publications found

Genes affected

CAPN1 (HGNC:1476): (calpain 1) 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 the large subunit of the ubiquitous enzyme, calpain 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

CAPN1 Gene-Disease associations (from GenCC):

• autosomal recessive spastic paraplegia type 76

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-65206824-G-A is Pathogenic according to our data. Variant chr11-65206824-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN1	NM_005186.4	c.1605+5G>A		splice_region_variant, intron_variant	Intron 14 of 21	ENST00000279247.11	NP_005177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN1	ENST00000279247.11	c.1605+5G>A		splice_region_variant, intron_variant	Intron 14 of 21	1	NM_005186.4	ENSP00000279247.7

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000132

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000116 AC: 28 AN: 242366 AF XY: 0.000137

Gnomad AFR exome AF: 0.0000676

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000104 AC: 151 AN: 1458686 Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 80 AN XY: 725384

African (AFR) AF: 0.0000299 AC: 1 AN: 33390

American (AMR) AF: 0.0000901 AC: 4 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39546

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52964

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000124 AC: 138 AN: 1110716

Other (OTH) AF: 0.0000498 AC: 3 AN: 60240

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74280

African (AFR) AF: 0.0000966 AC: 4 AN: 41398

American (AMR) AF: 0.000262 AC: 4 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.000962 AC: 2 AN: 2080

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive spastic paraplegia type 76 Pathogenic:10

Oct 14, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CAPN1 c.1605+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant leads to skipping of exon 14, confirmed by cDNA sequencing (e.g. Gan-Or_2016). The variant allele was found at a frequency of 0.00012 in 242366 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN1 causing Autosomal Recessive Spastic Paraplegia Type 76, allowing no conclusion about variant significance. c.1605+5G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Autosomal Recessive Spastic Paraplegia Type 76 (e.g. Gan-Or_2016, Benkirane_2021, Ek_2023), or in one compound heterozygous individual affected with a spinocerebellar ataxia (e.g. Baviera-Muoz_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 37273706, 36530930, 27153400). ClinVar contains an entry for this variant (Variation ID: 225768). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2018

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2019

Section for Clinical Neurogenetics, University of Tübingen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Predicted Consequence/Location: Intron variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.56 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000225768 /PMID: 27153400). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

Feb 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in loss-of-function (Gan-Or et al., 2016); This variant is associated with the following publications: (PMID: 30572172, 27153400, 32214227, 33726816, 33486633) -

Feb 04, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the CAPN1 gene demonstrated a sequence change located near the canonical splice donor site in intron 14, c.1605+5G>A. This sequence change has been described in the gnomAD database with a low population frequency of 0.012% (dbSNP rs375817528). This variant was identified in two symptomatic family members with spastic paraplegia in a compound heterozygous state with other frameshift variant (Gan-Or et al., 2016). Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the CAPN1 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively. -

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 14 of the CAPN1 gene. It does not directly change the encoded amino acid sequence of the CAPN1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs375817528, gnomAD 0.02%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 27153400, 32214227, 33486633; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 14, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 27153400). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.91
PhyloP100		1.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: 47

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375817528; hg19: chr11-64974295;