chr1-230747699-A-C

Position:

• chr1-230747699-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006615.3(CAPN9):​c.203A>C​(p.Lys68Thr) 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAPN9 NM_006615.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.78

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 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, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN9	NM_006615.3	c.203A>C	p.Lys68Thr	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.203A>C	p.Lys68Thr	missense_variant	1/20	1	NM_006615.3	ENSP00000271971.2
CAPN9	ENST00000354537.1	c.203A>C	p.Lys68Thr	missense_variant	1/19	1		ENSP00000346538.1
CAPN9	ENST00000366666.6	c.203A>C	p.Lys68Thr	missense_variant	1/18	1		ENSP00000355626.2
ENSG00000244137	ENST00000412344.1	n.381-36846T>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1460846 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

May 04, 2022

The c.203A>C (p.K68T) alteration is located in exon 1 (coding exon 1) of the CAPN9 gene. This alteration results from a A to C substitution at nucleotide position 203, causing the lysine (K) at amino acid position 68 to be replaced by a threonine (T). 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	0.74
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.8	H;.;H
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.69
MutPred		0.71		Loss of methylation at K68 (P = 0.0057);Loss of methylation at K68 (P = 0.0057);Loss of methylation at K68 (P = 0.0057);
MVP		0.75
MPC		0.50
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.89
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-230883445;