Genetic Variant CCZ1:p.Lys221Thr (chr7-5905233-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015622.6(CCZ1):c.662A>C(p.Lys221Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000838 in 1,550,924 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K221R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

CCZ1
NM_015622.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.19

Publications

0 publications found

Variant links:

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]

CCZ1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015622.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCZ1	NM_015622.6	MANE Select	c.662A>C	p.Lys221Thr	missense	Exon 7 of 15	NP_056437.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCZ1	ENST00000325974.9	TSL:1 MANE Select	c.662A>C	p.Lys221Thr	missense	Exon 7 of 15	ENSP00000325681.6	P86791
CCZ1	ENST00000928077.1		c.662A>C	p.Lys221Thr	missense	Exon 7 of 15	ENSP00000598136.1
CCZ1	ENST00000928076.1		c.662A>C	p.Lys221Thr	missense	Exon 7 of 15	ENSP00000598135.1

Frequencies

GnomAD3 genomes

AF:

0.0000141

AC:

AN:

142316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000544

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000171

AC:

AN:

233778

AF XY:

0.0000157

show subpopulations

Gnomad AFR exome

AF:

0.0000717

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000279

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000781

AC:

AN:

1408608

Hom.:

Cov.:

AF XY:

0.00000570

AC XY:

AN XY:

701584

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30198

American (AMR)

AF:

0.00

AC:

AN:

43018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25462

East Asian (EAS)

AF:

0.00

AC:

AN:

35030

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.00000927

AC:

AN:

1078232

Other (OTH)

AF:

0.00

AC:

AN:

58164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000141

AC:

AN:

142316

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

68824

show subpopulations

African (AFR)

AF:

0.0000544

AC:

AN:

36776

American (AMR)

AF:

0.00

AC:

AN:

14404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3382

East Asian (EAS)

AF:

0.00

AC:

AN:

4176

South Asian (SAS)

AF:

0.00

AC:

AN:

4066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66902

Other (OTH)

AF:

0.00

AC:

AN:

1954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

ExAC

AF:

0.0000168

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.0043

MetaRNN

Uncertain

0.72

MetaSVM

Benign

-1.0

PhyloP100

7.2

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.55

Sift

Benign

0.081

Sift4G

Uncertain

0.0060

Vest4

0.91

MVP

0.19

ClinPred

0.36

GERP RS

5.8

Varity_R

0.38

gMVP

0.71

Mutation Taster

=40/60

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over