1-230747509-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006615.3(CAPN9):c.13T>C(p.Tyr5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN9 NM_006615.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0510

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0419361).
• BP6: Variant 1-230747509-T-C is Benign according to our data. Variant chr1-230747509-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2622714.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN9	NM_006615.3	c.13T>C	p.Tyr5His	missense_variant	1/20	ENST00000271971.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN9	ENST00000271971.7	c.13T>C	p.Tyr5His	missense_variant	1/20	1	NM_006615.3	P1
CAPN9	ENST00000354537.1	c.13T>C	p.Tyr5His	missense_variant	1/19	1
CAPN9	ENST00000366666.6	c.13T>C	p.Tyr5His	missense_variant	1/18	1
	ENST00000412344.1	n.381-36656A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	12
Dann	Benign	0.49
DEOGEN2	Benign	0.033	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.17	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.14
MutPred		0.36		Loss of phosphorylation at Y5 (P = 0.0037);Loss of phosphorylation at Y5 (P = 0.0037);Loss of phosphorylation at Y5 (P = 0.0037);
MVP		0.14
MPC		0.11
ClinPred		0.046	T
GERP RS		-6.0
Varity_R		0.022
gMVP		0.45

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: chr1-230883255;