1-223712873-C-CCACGGTAGGAAGCG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001748.5(CAPN2):c.235_237+11dup variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,531,350 control chromosomes in the GnomAD database, including 64 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (60 hom.)
• Consequence: CAPN2 NM_001748.5 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.735

Genes affected

CAPN2 (HGNC:1479): (calpain 2) 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 2. Multiple heterogeneous transcriptional start sites in the 5' UTR have been reported. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 1-223712873-C-CCACGGTAGGAAGCG is Benign according to our data. Variant chr1-223712873-C-CCACGGTAGGAAGCG is described in ClinVar as [Benign]. Clinvar id is 790811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN2	NM_001748.5	c.235_237+11dup		frameshift_variant	1/21	ENST00000295006.6
CAPN2	XM_047431344.1	c.235_237+11dup		frameshift_variant	1/12
CAPN2	NM_001146068.2	c.4-4887_4-4874dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN2	ENST00000295006.6	c.235_237+11dup		frameshift_variant	1/21	1	NM_001748.5	P1
CAPN2	ENST00000433674.6	c.4-4887_4-4874dup		intron_variant		2
CAPN2	ENST00000434648.5	c.4-4887_4-4874dup		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 874 AN: 151914 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00827

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00533 AC: 795 AN: 149096 Hom.: 6 AF XY: 0.00524 AC XY: 435 AN XY: 83032

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00506

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00593

Gnomad OTH exome AF: 0.00259

GnomAD4 exome AF: 0.00773 AC: 10663 AN: 1379326 Hom.: 60 Cov.: 34 AF XY: 0.00756 AC XY: 5164 AN XY: 682966

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.00271

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00566

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.00838

Gnomad4 OTH exome AF: 0.00584

GnomAD4 genome AF: 0.00575 AC: 874 AN: 152024 Hom.: 4 Cov.: 32 AF XY: 0.00636 AC XY: 473 AN XY: 74320

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.00827

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00459 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs573919326; hg19: chr1-223900575;