NM_004055.5:c.44C>T

Variant names:

• chr11-77084930-C-T
• rs781943181
• NM_004055.5:c.44C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004055.5(CAPN5):​c.44C>T​(p.Ala15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CAPN5 NM_004055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• autosomal dominant neovascular inflammatory vitreoretinopathy

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059051245).
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN5	NM_004055.5	MANE Select	c.44C>T	p.Ala15Val	missense	Exon 2 of 13	NP_004046.2
	CAPN5	NM_001425321.1		c.44C>T	p.Ala15Val	missense	Exon 2 of 14	NP_001412250.1	E7EV01
	CAPN5	NM_001425322.1		c.44C>T	p.Ala15Val	missense	Exon 3 of 14	NP_001412251.1	A0A140VKH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN5	ENST00000648180.1	MANE Select	c.44C>T	p.Ala15Val	missense	Exon 2 of 13	ENSP00000498132.1	O15484
	CAPN5	ENST00000529629.5	TSL:1	c.44C>T	p.Ala15Val	missense	Exon 3 of 14	ENSP00000432332.1	O15484
	CAPN5	ENST00000886046.1		c.44C>T	p.Ala15Val	missense	Exon 2 of 14	ENSP00000556105.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251120 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461680 Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.017
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.28		Loss of disorder (P = 0.0868)
MVP		0.28
MPC		0.15
ClinPred		0.16	T
GERP RS		2.1
Varity_R		0.059
gMVP		0.43
Mutation Taster		=73/27	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: rs781943181; hg19: chr11-76795976;