7-5900340-T-G

Variant names:

• chr7-5900340-T-G
• rs1386289149
• NM_015622.6:c.177T>G

Variant summary

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

The NM_015622.6(CCZ1):​c.177T>G​(p.Ile59Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000702 in 1,424,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: CCZ1 NM_015622.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

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.177T>G	p.Ile59Met	missense_variant	Exon 2 of 15	ENST00000325974.9	NP_056437.4
CCZ1	XM_047420465.1	c.177T>G	p.Ile59Met	missense_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.177T>G	p.Ile59Met	missense_variant	Exon 2 of 15	1	NM_015622.6	ENSP00000325681.6
CCZ1	ENST00000628813.2	c.177T>G	p.Ile59Met	missense_variant	Exon 2 of 14	2		ENSP00000486988.1
CCZ1	ENST00000461592.1	n.252T>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
CCZ1	ENST00000478672.1	n.196T>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000702 AC: 10 AN: 1424098 Hom.: 0 Cov.: 31 AF XY: 0.00000706 AC XY: 5 AN XY: 708182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000531

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.12e-7

Gnomad4 OTH exome AF: 0.000118

GnomAD4 genome Cov.: 28

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.177T>G (p.I59M) alteration is located in exon 2 (coding exon 2) of the CCZ1 gene. This alteration results from a T to G substitution at nucleotide position 177, causing the isoleucine (I) at amino acid position 59 to be replaced by a methionine (M). 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	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0060	D;D
Vest4		0.78
MutPred		0.38		Loss of methylation at K58 (P = 0.0343);Loss of methylation at K58 (P = 0.0343);
MVP		0.30
ClinPred		0.99	D
GERP RS		2.0
Varity_R		0.37
gMVP		0.50

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: rs1386289149; hg19: chr7-5939971;