7-5910088-C-A

Position:

• chr7-5910088-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015622.6(CCZ1):​c.752C>A​(p.Ser251Tyr) 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCZ1 NM_015622.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCZ1	NM_015622.6	c.752C>A	p.Ser251Tyr	missense_variant	8/15	ENST00000325974.9	NP_056437.4
CCZ1	XM_047420465.1	c.752C>A	p.Ser251Tyr	missense_variant	8/11		XP_047276421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCZ1	ENST00000325974.9	c.752C>A	p.Ser251Tyr	missense_variant	8/15	1	NM_015622.6	ENSP00000325681	P1
CCZ1	ENST00000628813.2	c.*421C>A		3_prime_UTR_variant	7/14	2		ENSP00000486988
CCZ1	ENST00000483394.1	n.379C>A		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000141 AC: 2 AN: 1419410 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 707892

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome Cov.: 32

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

Sep 16, 2021

The c.752C>A (p.S251Y) alteration is located in exon 8 (coding exon 8) of the CCZ1 gene. This alteration results from a C to A substitution at nucleotide position 752, causing the serine (S) at amino acid position 251 to be replaced by a tyrosine (Y). 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	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0059	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0090	D
Vest4		0.89
MutPred		0.67		Gain of methylation at K246 (P = 0.0879);
MVP		0.17
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs1275039857; hg19: chr7-5949719;