Variant 1-230759516-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006615.3(CAPN9):c.288C>G(p.Asp96Glu) variant causes a missense change. 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: 33)

Consequence

CAPN9
NM_006615.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.75

Variant links:

Genes affected

CAPN9 (HGNC:1486): (calpain 9) Calpains are ubiquitous, well-conserved family of calcium-dependent, cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large subunit possesses a cysteine protease domain, and both subunits possess calcium-binding domains. Calpains have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. The protein encoded by this gene is expressed predominantly in stomach and small intestine and may have specialized functions in the digestive tract. This gene is thought to be associated with gastric cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CAPN9 links:

CAPN9 (HGNC:):

CAPN9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN9	NM_006615.3 linkuse as main transcript	c.288C>G	p.Asp96Glu	missense_variant	3/20	ENST00000271971.7	NP_006606.1	O14815-1Q6PIV8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CAPN9	ENST00000271971.7 linkuse as main transcript	c.288C>G	p.Asp96Glu	missense_variant	3/20	1	NM_006615.3	ENSP00000271971.2	O14815-1
CAPN9	ENST00000354537.1 linkuse as main transcript	c.288C>G	p.Asp96Glu	missense_variant	3/19	1		ENSP00000346538.1	O14815-2
CAPN9	ENST00000366666.6 linkuse as main transcript	c.214-3137C>G		intron_variant		1		ENSP00000355626.2	E7ESS6
ENSG00000244137	ENST00000412344.1 linkuse as main transcript	n.380+35597G>C		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243494

Hom.:

AF XY:

0.00000760

AC XY:

AN XY:

131576

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.288C>G (p.D96E) alteration is located in exon 3 (coding exon 3) of the CAPN9 gene. This alteration results from a C to G substitution at nucleotide position 288, causing the aspartic acid (D) at amino acid position 96 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

3.8

H;H

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0050

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.82

Gain of catalytic residue at D96 (P = 0.059);Gain of catalytic residue at D96 (P = 0.059);

MVP

0.58

MPC

0.19

ClinPred

0.99

GERP RS

5.2

Varity_R

0.91

gMVP

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over