16-547094-G-C

Position:

• chr16-547094-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005632.3(CAPN15):​c.256G>C​(p.Val86Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,435,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 7.0e-7 (0 hom.)
• Consequence: CAPN15 NM_005632.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

Genes affected

CAPN15 (HGNC:11182): (calpain 15) This gene encodes a protein containing zinc-finger-like repeats and a calpain-like protease domain. The encoded protein may function as a transcription factor, RNA-binding protein, or in protein-protein interactions during visual system development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123356104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN15	NM_005632.3	c.256G>C	p.Val86Leu	missense_variant	4/14	ENST00000219611.7	NP_005623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN15	ENST00000219611.7	c.256G>C	p.Val86Leu	missense_variant	4/14	1	NM_005632.3	ENSP00000219611.2
CAPN15	ENST00000637507.1	c.460G>C	p.Val154Leu	missense_variant	2/2	5		ENSP00000490480.1
CAPN15	ENST00000562370.5	c.256G>C	p.Val86Leu	missense_variant	3/3	2		ENSP00000456017.1
CAPN15	ENST00000568988.5	c.-314-465G>C		intron_variant		3		ENSP00000457030.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435986 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712668

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000369 Hom.: 0

Bravo AF: 0.00000378

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

Aug 19, 2023

The c.256G>C (p.V86L) alteration is located in exon 4 (coding exon 1) of the CAPN15 gene. This alteration results from a G to C substitution at nucleotide position 256, causing the valine (V) at amino acid position 86 to be replaced by a leucine (L). 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	Benign	0.088
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.0027	T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.64	.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.42	N;N;.
REVEL	Benign	0.16
Sift	Benign	0.24	T;T;.
Sift4G	Benign	0.70	T;T;.
Polyphen		0.0	.;B;.
Vest4		0.12
MutPred		0.29		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);.;
MVP		0.13
ClinPred		0.048	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.039
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs1236101518; hg19: chr16-597094;