NM_004930.5:c.320A>G

Variant names:

• chr1-19378549-T-C
• NM_004930.5:c.320A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004930.5(CAPZB):​c.320A>G​(p.Tyr107Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAPZB NM_004930.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004930.5. 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
	CAPZB	NM_004930.5	MANE Select	c.320A>G	p.Tyr107Cys	missense	Exon 4 of 9	NP_004921.1	A0A384MR50
	CAPZB	NM_001282162.2		c.407A>G	p.Tyr136Cys	missense	Exon 4 of 9	NP_001269091.1	B1AK88
	CAPZB	NM_001206540.3		c.320A>G	p.Tyr107Cys	missense	Exon 4 of 10	NP_001193469.1	P47756-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPZB	ENST00000264202.8	TSL:1 MANE Select	c.320A>G	p.Tyr107Cys	missense	Exon 4 of 9	ENSP00000264202.7	P47756-2
	CAPZB	ENST00000375144.6	TSL:1	c.320A>G	p.Tyr107Cys	missense	Exon 4 of 8	ENSP00000364286.2	B1AK87
	CAPZB	ENST00000433834.5	TSL:2	c.407A>G	p.Tyr136Cys	missense	Exon 4 of 9	ENSP00000401010.1	B1AK88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444130 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 719816

African (AFR) AF: 0.00 AC: 0 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095732

Other (OTH) AF: 0.00 AC: 0 AN: 59828

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		6.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.87		Loss of phosphorylation at Y136 (P = 0.0437)
MVP		0.80
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.84
gMVP		0.97
Mutation Taster		=22/78	disease causing

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

hg19: chr1-19705043;