16-547059-C-T

Position:

• chr16-547059-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005632.3(CAPN15):​c.221C>T​(p.Ala74Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,603,302 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0049 (23 hom.)
• Consequence: CAPN15 NM_005632.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.494

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036720634).
• BP6: Variant 16-547059-C-T is Benign according to our data. Variant chr16-547059-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2645791.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (573/152390) while in subpopulation NFE AF= 0.00588 (400/68044). AF 95% confidence interval is 0.0054. There are 2 homozygotes in gnomad4. There are 263 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN15	NM_005632.3	c.221C>T	p.Ala74Val	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.221C>T	p.Ala74Val	missense_variant	4/14	1	NM_005632.3	ENSP00000219611.2
CAPN15	ENST00000637507.1	c.425C>T	p.Ala142Val	missense_variant	2/2	5		ENSP00000490480.1
CAPN15	ENST00000562370.5	c.221C>T	p.Ala74Val	missense_variant	3/3	2		ENSP00000456017.1
CAPN15	ENST00000568988.5	c.-314-500C>T		intron_variant		3		ENSP00000457030.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 573 AN: 152272 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00360 AC: 826 AN: 229248 Hom.: 0 AF XY: 0.00349 AC XY: 440 AN XY: 126012

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.000836

Gnomad ASJ exome AF: 0.00425

Gnomad EAS exome AF: 0.0000577

Gnomad SAS exome AF: 0.00211

Gnomad FIN exome AF: 0.00649

Gnomad NFE exome AF: 0.00529

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00488 AC: 7085 AN: 1450912 Hom.: 23 Cov.: 32 AF XY: 0.00472 AC XY: 3403 AN XY: 721544

Gnomad4 AFR exome AF: 0.000630

Gnomad4 AMR exome AF: 0.000838

Gnomad4 ASJ exome AF: 0.00457

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00222

Gnomad4 FIN exome AF: 0.00709

Gnomad4 NFE exome AF: 0.00555

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00376 AC: 573 AN: 152390 Hom.: 2 Cov.: 34 AF XY: 0.00353 AC XY: 263 AN XY: 74520

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.00588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00487 Hom.: 0

Bravo AF: 0.00320

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00208 AC: 9

ESP6500EA AF: 0.00503 AC: 43

ExAC AF: 0.00357 AC: 428

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

CAPN15: BP4 -

CAPN15-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.34
DANN	Benign	0.89
DEOGEN2	Benign	0.010	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.26	.;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Benign	0.20
Sift	Benign	0.37	T;T;.
Sift4G	Benign	0.36	T;T;.
Polyphen		0.0010	.;B;.
Vest4		0.039
MVP		0.69
ClinPred		0.000095	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141227716; hg19: chr16-597059; COSMIC: COSV54837852; COSMIC: COSV54837852;