7-116893014-A-C

Position:

• chr7-116893014-A-C

Variant summary

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

The NM_006136.3(CAPZA2):​c.124A>C​(p.Asn42His) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,446,512 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (1 hom.)
• Consequence: CAPZA2 NM_006136.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPZA2	NM_006136.3	c.124A>C	p.Asn42His	missense_variant	3/10	ENST00000361183.8	NP_006127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPZA2	ENST00000361183.8	c.124A>C	p.Asn42His	missense_variant	3/10	1	NM_006136.3	ENSP00000354947.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446512 Hom.: 1 Cov.: 26 AF XY: 0.00000278 AC XY: 2 AN XY: 719956

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: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Dec 05, 2022

The c.124A>C (p.N42H) alteration is located in exon 3 (coding exon 3) of the CAPZA2 gene. This alteration results from a A to C substitution at nucleotide position 124, causing the asparagine (N) at amino acid position 42 to be replaced by a histidine (H). 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	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.0014	D
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.60
MutPred		0.65		Loss of stability (P = 0.0422);Loss of stability (P = 0.0422);Loss of stability (P = 0.0422);
MVP		0.51
MPC		0.87
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116533068;