7-5912923-C-T

Position:

• chr7-5912923-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015622.6(CCZ1):​c.923C>T​(p.Thr308Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,445,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCZ1 NM_015622.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33342952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCZ1	NM_015622.6	c.923C>T	p.Thr308Ile	missense_variant	10/15	ENST00000325974.9	NP_056437.4
CCZ1	XM_047420465.1	c.923C>T	p.Thr308Ile	missense_variant	10/11		XP_047276421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCZ1	ENST00000325974.9	c.923C>T	p.Thr308Ile	missense_variant	10/15	1	NM_015622.6	ENSP00000325681	P1
CCZ1	ENST00000628813.2	c.*592C>T		3_prime_UTR_variant	9/14	2		ENSP00000486988

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445000 Hom.: 0 Cov.: 28 AF XY: 0.00000278 AC XY: 2 AN XY: 718776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000234

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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 06, 2023

The c.923C>T (p.T308I) alteration is located in exon 10 (coding exon 10) of the CCZ1 gene. This alteration results from a C to T substitution at nucleotide position 923, causing the threonine (T) at amino acid position 308 to be replaced by an isoleucine (I). 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	Benign	-0.0054	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T
Eigen	Benign	0.0087
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.86	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.076
Sift	Benign	0.15	T
Sift4G	Benign	0.18	T
Vest4		0.53
MutPred		0.45		Gain of catalytic residue at T308 (P = 0.0572);
MVP		0.082
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.083
gMVP		0.34

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: rs1583188333; hg19: chr7-5952554; COSMIC: COSV58075236; COSMIC: COSV58075236;