7-5900380-A-G

Variant names:

• chr7-5900380-A-G
• rs1207944249
• NM_015622.6:c.217A>G

Variant summary

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

The NM_015622.6(CCZ1):​c.217A>G​(p.Arg73Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000028 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCZ1 NM_015622.6 missense, splice_region
• Scores: Splicing: ADA: 0.8892
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.94

Genes affected

CCZ1 (HGNC:21691): (CCZ1 homolog, vacuolar protein trafficking and biogenesis associated) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in vesicle-mediated transport. Located in intracellular membrane-bounded organelle. Part of Mon1-Ccz1 complex. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
CCZ1	NM_015622.6	c.217A>G	p.Arg73Gly	missense_variant, splice_region_variant	Exon 2 of 15	ENST00000325974.9	NP_056437.4
CCZ1	XM_047420465.1	c.217A>G	p.Arg73Gly	missense_variant, splice_region_variant	Exon 2 of 11		XP_047276421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCZ1	ENST00000325974.9	c.217A>G	p.Arg73Gly	missense_variant, splice_region_variant	Exon 2 of 15	1	NM_015622.6	ENSP00000325681.6
CCZ1	ENST00000628813.2	c.217A>G	p.Arg73Gly	missense_variant, splice_region_variant	Exon 2 of 14	2		ENSP00000486988.1
CCZ1	ENST00000461592.1	n.292A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
CCZ1	ENST00000478672.1	n.236A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000283 AC: 4 AN: 1413616 Hom.: 2 Cov.: 31 AF XY: 0.00000284 AC XY: 2 AN XY: 703832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217A>G (p.R73G) alteration is located in exon 2 (coding exon 2) of the CCZ1 gene. This alteration results from a A to G substitution at nucleotide position 217, causing the arginine (R) at amino acid position 73 to be replaced by a glycine (G). 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
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.041
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.0078	T
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.28
Sift	Benign	0.31	T;.
Sift4G	Benign	0.15	T;D
Vest4		0.83
MutPred		0.69		Loss of catalytic residue at R73 (P = 0.0517);Loss of catalytic residue at R73 (P = 0.0517);
MVP		0.15
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.41
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1207944249; hg19: chr7-5940011;