1-230747624-T-G

Position:

• chr1-230747624-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006615.3(CAPN9):​c.128T>G​(p.Phe43Cys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN9 NM_006615.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN9	NM_006615.3	c.128T>G	p.Phe43Cys	missense_variant	1/20	ENST00000271971.7	NP_006606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN9	ENST00000271971.7	c.128T>G	p.Phe43Cys	missense_variant	1/20	1	NM_006615.3	ENSP00000271971.2
CAPN9	ENST00000354537.1	c.128T>G	p.Phe43Cys	missense_variant	1/19	1		ENSP00000346538.1
CAPN9	ENST00000366666.6	c.128T>G	p.Phe43Cys	missense_variant	1/18	1		ENSP00000355626.2
ENSG00000244137	ENST00000412344.1	n.381-36771A>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.128T>G (p.F43C) alteration is located in exon 1 (coding exon 1) of the CAPN9 gene. This alteration results from a T to G substitution at nucleotide position 128, causing the phenylalanine (F) at amino acid position 43 to be replaced by a cysteine (C). 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	0.90
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.3	H;.;H
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.92
MutPred		0.90		Gain of disorder (P = 0.1431);Gain of disorder (P = 0.1431);Gain of disorder (P = 0.1431);
MVP		0.69
MPC		0.55
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-230883370;