11-65210073-T-G

Variant names:

• chr11-65210073-T-G
• rs752166957
• NM_005186.4:c.1919T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005186.4(CAPN1):​c.1919T>G​(p.Met640Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN1 NM_005186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• Publications: 1 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

ENSG00000301154 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN1	NM_005186.4	c.1919T>G	p.Met640Arg	missense_variant	Exon 19 of 22	ENST00000279247.11	NP_005177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN1	ENST00000279247.11	c.1919T>G	p.Met640Arg	missense_variant	Exon 19 of 22	1	NM_005186.4	ENSP00000279247.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met640Arg variant in CAPN1 has not been previously reported in the literat ure and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, the clinical significance of the p.Met640Arg variant is uncertain.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D;D;D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;.;.;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Pathogenic	3.4	M;M;M;M;M
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.95
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.95
gMVP		0.99
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs752166957; hg19: chr11-64977544;