rs375817528

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV005203107: 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). no" and additional evidence is available in ClinVar.

• 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005203107: 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). no; SCV001766837: Non-canonical splice site variant demonstrated to result in loss-of-function (Gan-Or et al., 2016); SCV002143741: 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).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005186.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN1	NM_005186.4	MANE Select	c.1605+5G>A		splice_region intron	N/A	NP_005177.2
	CAPN1	NM_001198868.2		c.1605+5G>A		splice_region intron	N/A	NP_001185797.1	P07384
	CAPN1	NM_001198869.2		c.1605+5G>A		splice_region intron	N/A	NP_001185798.1	P07384

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN1	ENST00000279247.11	TSL:1 MANE Select	c.1605+5G>A		splice_region intron	N/A	ENSP00000279247.7	P07384
	CAPN1	ENST00000524773.5	TSL:1	c.1605+5G>A		splice_region intron	N/A	ENSP00000434176.1	P07384
	CAPN1	ENST00000527323.5	TSL:1	c.1605+5G>A		splice_region intron	N/A	ENSP00000431984.1	P07384

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Autosomal recessive spastic paraplegia type 76 (10)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

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;