Genetic Variant NM_022034.6:c.818-12_818-9delTTTT (chr10-122836358-GAAAA-G) – 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_022034.6(CUZD1):c.818-12_818-9delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,196,832 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0023 ( 0 hom. )

Consequence

CUZD1
NM_022034.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

Publications

1 publications found

Variant links:

Genes affected

CUZD1 (HGNC:17937): (CUB and zona pellucida like domains 1) Predicted to be involved in trypsinogen activation. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

CUZD1 Gene-Disease associations (from GenCC):

schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

CUZD1 links:

ENSG00000286088 (HGNC:):

ENSG00000286088 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Variant has high frequency in the SAS (0.00644) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CUZD1	NM_022034.6 link	c.818-12_818-9delTTTT	intron_variant	Intron 5 of 8	ENST00000392790.6	NP_071317.2	Q86UP6-1
CUZD1	NR_037912.2 link	n.681-12_681-9delTTTT	intron_variant	Intron 4 of 7
FAM24B-CUZD1	NR_037915.1 link	n.1494-12_1494-9delTTTT	intron_variant	Intron 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUZD1	ENST00000392790.6 link	c.818-12_818-9delTTTT		intron_variant	Intron 5 of 8	1	NM_022034.6	ENSP00000376540.1		Q86UP6-1
ENSG00000286088	ENST00000368904.6 link	n.818-12_818-9delTTTT		intron_variant	Intron 6 of 9	1		ENSP00000357900.2		A0A499FIG0

Frequencies

GnomAD3 genomes

AF:

0.0000284

AC:

AN:

141016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000261

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:

0.000375

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00989

AC:

703

AN:

71052

AF XY:

0.0108

show subpopulations

Gnomad AFR exome

AF:

0.00643

Gnomad AMR exome

AF:

0.0120

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.0128

Gnomad FIN exome

AF:

0.00829

Gnomad NFE exome

AF:

0.00907

Gnomad OTH exome

AF:

0.00533

GnomAD4 exome

AF:

0.00228

AC:

2406

AN:

1055812

Hom.:

AF XY:

0.00253

AC XY:

1308

AN XY:

517728

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00169

AC:

AN:

21882

American (AMR)

AF:

0.00655

AC:

106

AN:

16182

Ashkenazi Jewish (ASJ)

AF:

0.00321

AC:

AN:

16486

East Asian (EAS)

AF:

0.00261

AC:

AN:

28684

South Asian (SAS)

AF:

0.00707

AC:

327

AN:

46268

European-Finnish (FIN)

AF:

0.00389

AC:

129

AN:

33180

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

3596

European-Non Finnish (NFE)

AF:

0.00186

AC:

1569

AN:

845610

Other (OTH)

AF:

0.00239

AC:

105

AN:

43924

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.260

Heterozygous variant carriers

279

558

838

1117

1396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<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:

0.0000284

AC:

AN:

141020

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

68020

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000261

AC:

AN:

38310

American (AMR)

AF:

0.00

AC:

AN:

14216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3352

East Asian (EAS)

AF:

0.00

AC:

AN:

4854

South Asian (SAS)

AF:

0.00

AC:

AN:

4388

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

7996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64808

Other (OTH)

AF:

0.00

AC:

AN:

1928

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over