Genetic Variant CAPN1:p.Met640Thr (chr11-65210073-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005186.4(CAPN1):c.1919T>C(p.Met640Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M640R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CAPN1
NM_005186.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.88

Publications

1 publications found

Variant links:

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

CAPN1 links:

ENSG00000301154 (HGNC:):

ENSG00000301154 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN1	NM_005186.4 link	c.1919T>C	p.Met640Thr	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 link	c.1919T>C	p.Met640Thr	missense_variant	Exon 19 of 22	1	NM_005186.4	ENSP00000279247.7

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150630

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000389

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248528

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460818

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726670

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111828

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000199

AC:

AN:

150630

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40942

American (AMR)

AF:

0.00

AC:

AN:

14966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.000389

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67690

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;D;D;D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

.;.;.;.;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

-0.035

MutationAssessor

Pathogenic

3.4

M;M;M;M;M

PhyloP100

7.9

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.4

D;D;D;D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

0.99

D;D;D;D;D

Vest4

0.93

MutPred

0.67

Gain of phosphorylation at M640 (P = 0.0346);Gain of phosphorylation at M640 (P = 0.0346);Gain of phosphorylation at M640 (P = 0.0346);Gain of phosphorylation at M640 (P = 0.0346);Gain of phosphorylation at M640 (P = 0.0346);

MVP

0.89

MPC

1.1

ClinPred

0.99

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.86

gMVP

0.95

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over