7-5905242-C-T

Variant names:

• chr7-5905242-C-T
• rs758549688
• NM_015622.6:c.671C>T

Variant summary

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

The NM_015622.6(CCZ1):​c.671C>T​(p.Ala224Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCZ1 NM_015622.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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.671C>T	p.Ala224Val	missense_variant	Exon 7 of 15	ENST00000325974.9	NP_056437.4
CCZ1	XM_047420465.1	c.671C>T	p.Ala224Val	missense_variant	Exon 7 of 11		XP_047276421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCZ1	ENST00000325974.9	c.671C>T	p.Ala224Val	missense_variant	Exon 7 of 15	1	NM_015622.6	ENSP00000325681.6
CCZ1	ENST00000628813.2	c.*340C>T		3_prime_UTR_variant	Exon 6 of 14	2		ENSP00000486988.1
CCZ1	ENST00000483394.1	n.298C>T		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD3 exomes AF: 0.0000175 AC: 4 AN: 229078 Hom.: 0 AF XY: 0.0000160 AC XY: 2 AN XY: 124894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000286 AC: 4 AN: 1400914 Hom.: 0 Cov.: 26 AF XY: 0.00000287 AC XY: 2 AN XY: 697502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000944

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: 0.00

GnomAD4 genome Cov.: 27

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671C>T (p.A224V) alteration is located in exon 7 (coding exon 7) of the CCZ1 gene. This alteration results from a C to T substitution at nucleotide position 671, causing the alanine (A) at amino acid position 224 to be replaced by a valine (V). 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	0.071	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	0.065
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.0079	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.91	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.18
Sift	Benign	0.35	T
Sift4G	Benign	0.23	T
Vest4		0.72
MutPred		0.66		Loss of catalytic residue at A224 (P = 0.0339);
MVP		0.17
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs758549688; hg19: chr7-5944873;