chr11-77084909-A-T

Variant names:

• chr11-77084909-A-T
• rs1270133592
• NM_004055.5:c.23A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004055.5(CAPN5):​c.23A>T​(p.Tyr8Phe) 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. 15/22 in silico tools predict a benign 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. Y8C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAPN5 NM_004055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48
• Publications: 0 publications found

Genes affected

CAPN5 (HGNC:1482): (calpain 5) Calpains are calcium-dependent cysteine proteases involved in signal transduction in a variety of cellular processes. A functional calpain protein consists of an invariant small subunit and 1 of a family of large subunits. CAPN5 is one of the large subunits. Unlike some of the calpains, CAPN5 and CAPN6 lack a calmodulin-like domain IV. Because of the significant similarity to Caenorhabditis elegans sex determination gene tra-3, CAPN5 is also called as HTRA3. [provided by RefSeq, Jul 2008]

CAPN5 Gene-Disease associations (from GenCC):

• CAPN5-related vitreoretinopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant neovascular inflammatory vitreoretinopathy

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1058059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN5	NM_004055.5	c.23A>T	p.Tyr8Phe	missense_variant	Exon 2 of 13	ENST00000648180.1	NP_004046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN5	ENST00000648180.1	c.23A>T	p.Tyr8Phe	missense_variant	Exon 2 of 13		NM_004055.5	ENSP00000498132.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.73
DEOGEN2	Benign	0.035	T;T;T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	.;D;.;D;D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.80	N;.;N;N;.
PhyloP100		3.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.030	N;N;.;N;N
REVEL	Benign	0.094
Sift	Benign	1.0	T;T;.;T;T
Sift4G	Benign	1.0	T;T;.;T;T
Polyphen		0.028	B;.;B;B;B
Vest4		0.40
MutPred		0.60		Loss of phosphorylation at Y8 (P = 0.0344);Loss of phosphorylation at Y8 (P = 0.0344);Loss of phosphorylation at Y8 (P = 0.0344);Loss of phosphorylation at Y8 (P = 0.0344);Loss of phosphorylation at Y8 (P = 0.0344);
MVP		0.40
MPC		0.15
ClinPred		0.74	D
GERP RS		5.0
Varity_R		0.20
gMVP		0.50
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs1270133592; hg19: chr11-76795955;