1-19419657-G-A

Variant summary

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

The NM_004930.5(CAPZB):c.93+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,565,588 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (39 hom.)
• Consequence: CAPZB NM_004930.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00008451
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.849

Genes affected

CAPZB (HGNC:1491): (capping actin protein of muscle Z-line subunit beta) This gene encodes the beta subunit of the barbed-end actin binding protein, which belongs to the F-actin capping protein family. The capping protein is a heterodimeric actin capping protein that blocks actin filament assembly and disassembly at the fast growing (barbed) filament ends and functions in regulating actin filament dynamics as well as in stabilizing actin filament lengths in muscle and nonmuscle cells. A pseudogene of this gene is located on the long arm of chromosome 2. Multiple alternatively spliced transcript variants encoding different isoforms have been found.[provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-19419657-G-A is Benign according to our data. Variant chr1-19419657-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2638432.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-19419657-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00438 (6196/1413250) while in subpopulation MID AF= 0.0233 (133/5700). AF 95% confidence interval is 0.0201. There are 39 homozygotes in gnomad4_exome. There are 3250 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd at 576 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPZB	NM_004930.5	c.93+4C>T		splice_donor_region_variant, intron_variant		ENST00000264202.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPZB	ENST00000264202.8	c.93+4C>T		splice_donor_region_variant, intron_variant		1	NM_004930.5	P3

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 576 AN: 152220 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00530 AC: 1109 AN: 209130 Hom.: 12 AF XY: 0.00565 AC XY: 638 AN XY: 112878

Gnomad AFR exome AF: 0.000507

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.0000655

Gnomad SAS exome AF: 0.00925

Gnomad FIN exome AF: 0.00237

Gnomad NFE exome AF: 0.00437

Gnomad OTH exome AF: 0.00673

GnomAD4 exome AF: 0.00438 AC: 6196 AN: 1413250 Hom.: 39 Cov.: 26 AF XY: 0.00463 AC XY: 3250 AN XY: 702162

Gnomad4 AFR exome AF: 0.000745

Gnomad4 AMR exome AF: 0.00312

Gnomad4 ASJ exome AF: 0.0302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00851

Gnomad4 FIN exome AF: 0.00201

Gnomad4 NFE exome AF: 0.00369

Gnomad4 OTH exome AF: 0.00619

GnomAD4 genome AF: 0.00377 AC: 575 AN: 152338 Hom.: 8 Cov.: 33 AF XY: 0.00357 AC XY: 266 AN XY: 74494

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00456 Hom.: 1

Bravo AF: 0.00391

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

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

Jan 01, 2023

CAPZB: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.0030
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000085
dbscSNV1_RF	Benign	0.010
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: rs147095059; hg19: chr1-19746151; COSMIC: COSV51650476; COSMIC: COSV51650476;