NM_015622.6:c.217A>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73M) has been classified 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015622.6. 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
	CCZ1	NM_015622.6	MANE Select	c.217A>G	p.Arg73Gly	missense splice_region	Exon 2 of 15	NP_056437.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCZ1	ENST00000325974.9	TSL:1 MANE Select	c.217A>G	p.Arg73Gly	missense splice_region	Exon 2 of 15	ENSP00000325681.6	P86791
	CCZ1	ENST00000928077.1		c.217A>G	p.Arg73Gly	missense splice_region	Exon 2 of 15	ENSP00000598136.1
	CCZ1	ENST00000928076.1		c.217A>G	p.Arg73Gly	missense splice_region	Exon 2 of 15	ENSP00000598135.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32388

American (AMR) AF: 0.0000537 AC: 2 AN: 37238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25408

East Asian (EAS) AF: 0.00 AC: 0 AN: 37428

South Asian (SAS) AF: 0.00 AC: 0 AN: 82136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1083244

Other (OTH) AF: 0.00 AC: 0 AN: 58786

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

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	Uncertain	0.50
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
MetaSVM	Benign	-1.0	T
PhyloP100		8.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.31	T
Sift4G	Benign	0.15	T
Vest4		0.83
MutPred		0.69		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
Mutation Taster		=199/101	polymorphism

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

Other links and lift over

dbSNP: rs1207944249; hg19: chr7-5940011;