7-5900858-G-A

Variant names:

• chr7-5900858-G-A
• rs910812692
• NM_015622.6:c.316G>A

Variant summary

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

The NM_015622.6(CCZ1):​c.316G>A​(p.Val106Ile) 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: 26)
  • Exomes 𝑓: 0.0000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCZ1 NM_015622.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.35

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.316G>A	p.Val106Ile	missense_variant	Exon 4 of 15	ENST00000325974.9	NP_056437.4
CCZ1	XM_047420465.1	c.316G>A	p.Val106Ile	missense_variant	Exon 4 of 11		XP_047276421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCZ1	ENST00000325974.9	c.316G>A	p.Val106Ile	missense_variant	Exon 4 of 15	1	NM_015622.6	ENSP00000325681.6
CCZ1	ENST00000628813.2	c.222G>A	p.Leu74Leu	synonymous_variant	Exon 3 of 14	2		ENSP00000486988.1
CCZ1	ENST00000478672.1	n.623G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
CCZ1	ENST00000461592.1	n.*225G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000243 AC: 3 AN: 1233364 Hom.: 0 Cov.: 19 AF XY: 0.00000326 AC XY: 2 AN XY: 613106

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: 0.00000315

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.316G>A (p.V106I) alteration is located in exon 4 (coding exon 4) of the CCZ1 gene. This alteration results from a G to A substitution at nucleotide position 316, causing the valine (V) at amino acid position 106 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	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0053	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.95	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.19
Sift	Benign	0.25	T
Sift4G	Benign	0.20	T
Vest4		0.63
MutPred		0.52		Loss of disorder (P = 0.236);
MVP		0.16
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.16
gMVP		0.24

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: rs910812692; hg19: chr7-5940489;