rs1130685

Variant names:

• chr7-116888181-G-A
• rs1130685
• NM_006136.3:c.94G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006136.3(CAPZA2):​c.94G>A​(p.Val32Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CAPZA2 NM_006136.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64
• Publications: 0 publications found

Genes affected

CAPZA2 (HGNC:1490): (capping actin protein of muscle Z-line subunit alpha 2) The protein encoded by this gene is a member of the F-actin capping protein alpha subunit family. It is the alpha subunit of the barbed-end actin binding protein Cap Z. By capping the barbed end of actin filaments, Cap Z regulates the growth of the actin filaments at the barbed end. [provided by RefSeq, Jul 2008]

CAPZA2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.8416 (below the threshold of 3.09). Trascript score misZ: 1.2445 (below the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006136.3. 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
	CAPZA2	NM_006136.3	MANE Select	c.94G>A	p.Val32Ile	missense	Exon 2 of 10	NP_006127.1	A4D0V4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPZA2	ENST00000361183.8	TSL:1 MANE Select	c.94G>A	p.Val32Ile	missense	Exon 2 of 10	ENSP00000354947.2	P47755-1
	CAPZA2	ENST00000464223.5	TSL:1	c.27G>A	p.Arg9Arg	synonymous	Exon 2 of 4	ENSP00000420640.1	C9JCZ4
	CAPZA2	ENST00000484325.1	TSL:1	c.27G>A	p.Arg9Arg	synonymous	Exon 3 of 5	ENSP00000418262.1	C9J7V0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250244 AF XY: 0.00000739

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: 6.87e-7 AC: 1 AN: 1456202 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724892

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108084

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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	0.73
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0084	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.91	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.69
MutPred		0.78		Loss of loop (P = 0.2897)
MVP		0.38
MPC		1.1
ClinPred		0.87	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.77
Mutation Taster		=78/22	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: rs1130685; hg19: chr7-116528235;