1-223745429-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP3 BP4_Strong BP6_Moderate

The NM_001748.5(CAPN2):c.550G>A(p.Ala184Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,614,184 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: CAPN2 NM_001748.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.92

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.05486685).
• BP6: Variant 1-223745429-G-A is Benign according to our data. Variant chr1-223745429-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 719166.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN2	NM_001748.5	c.550G>A	p.Ala184Thr	missense_variant	4/21	ENST00000295006.6
CAPN2	NM_001146068.2	c.316G>A	p.Ala106Thr	missense_variant	4/21
CAPN2	XM_047431344.1	c.550G>A	p.Ala184Thr	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN2	ENST00000295006.6	c.550G>A	p.Ala184Thr	missense_variant	4/21	1	NM_001748.5	P1
CAPN2	ENST00000433674.6	c.316G>A	p.Ala106Thr	missense_variant	4/21	2
CAPN2	ENST00000434648.5	c.316G>A	p.Ala106Thr	missense_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000366 AC: 92 AN: 251398 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135868

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000172 AC: 251 AN: 1461860 Hom.: 1 Cov.: 32 AF XY: 0.000128 AC XY: 93 AN XY: 727234

Gnomad4 AFR exome AF: 0.00385

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.00153 AC XY: 114 AN XY: 74480

Gnomad4 AFR AF: 0.00498

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000770 Hom.: 0

Bravo AF: 0.00165

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000428 AC: 52

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.89
MVP		0.96
MPC		0.43
ClinPred		0.21	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.94
gMVP		0.85

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: rs147235023; hg19: chr1-223933131;