7-5900557-G-C

Position:

• chr7-5900557-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015622.6(CCZ1):​c.303G>C​(p.Trp101Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 26)
• Consequence: CCZ1 NM_015622.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.40

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]

CCZ1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCZ1	NM_015622.6	c.303G>C	p.Trp101Cys	missense_variant	3/15	ENST00000325974.9	NP_056437.4
CCZ1	XM_047420465.1	c.303G>C	p.Trp101Cys	missense_variant	3/11		XP_047276421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCZ1	ENST00000325974.9	c.303G>C	p.Trp101Cys	missense_variant	3/15	1	NM_015622.6	ENSP00000325681.6
CCZ1	ENST00000628813.2	c.218+176G>C		intron_variant		2		ENSP00000486988.1
CCZ1	ENST00000461592.1	n.469G>C		non_coding_transcript_exon_variant	2/2	2
CCZ1	ENST00000478672.1	n.322G>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 26

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

Jun 28, 2023

The c.303G>C (p.W101C) alteration is located in exon 3 (coding exon 3) of the CCZ1 gene. This alteration results from a G to C substitution at nucleotide position 303, causing the tryptophan (W) at amino acid position 101 to be replaced by a cysteine (C). 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	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.98
MutPred		0.89		Gain of disorder (P = 0.0262);
MVP		0.38
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.87

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-5940188;