Genetic Variant CASC8:n.547-1875_547-1874dupGT (chr8-127325027-T-TAC) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The ENST00000501396.6(CASC8):n.547-1875_547-1874dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 36,346 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as association (no stars).

Frequency

Genomes: 𝑓 0.024 ( 2 hom., cov: 25)

Consequence

CASC8
ENST00000501396.6 intron

Scores

Not classified

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 0.131

Publications

0 publications found

Variant links:

Genes affected

CASC8 (HGNC:45129): (cancer susceptibility 8)

CASC8 links:

POU5F1B (HGNC:9223): (POU class 5 homeobox 1B) This intronless gene was thought to be a transcribed pseudogene of POU class 5 homeobox 1, however, it has been reported that this gene can encode a functional protein. The encoded protein is nearly the same length as and highly similar to the POU class 5 homeobox 1 transcription factor, has been shown to be a weak transcriptional activator and may play a role in carcinogenesis and eye development. [provided by RefSeq, Apr 2009]

POU5F1B links:

PCAT1 (HGNC:43022): (prostate cancer associated transcript 1) This gene produces a long non-coding RNA that promotes cell proliferation and is upregulated in prostate, colorectal, and other cancers. This RNA negatively regulates the BRCA2 tumor suppressor protein and positively regulates Myc oncoprotein. It contains binding sites for microRNAs, and may act as a sponge for microRNAs that regulate cell growth pathways. [provided by RefSeq, Dec 2017]

PCAT1 links:

CASC21 (HGNC:49836): (cancer susceptibility 21)

CASC21 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0239 (869/36346) while in subpopulation NFE AF = 0.0326 (599/18392). AF 95% confidence interval is 0.0304. There are 2 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC21	NR_117099.1 link	n.302+2802_302+2803dupAC		intron_variant	Intron 2 of 3
CASC8	NR_117100.1 link	n.1177-34969_1177-34968dupGT		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CASC8	ENST00000501396.6 link	n.547-1875_547-1874dupGT	intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5 link	n.1177-34969_1177-34968dupGT	intron_variant	Intron 5 of 5	1
CASC8	ENST00000523825.3 link	n.547-34969_547-34968dupGT	intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

870

AN:

36294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00627

Gnomad AMI

AF:

0.00311

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00117

Gnomad EAS

AF:

0.000500

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.0686

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0326

Gnomad OTH

AF:

0.0126

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0239

AC:

869

AN:

36346

Hom.:

Cov.:

AF XY:

0.0248

AC XY:

429

AN XY:

17284

show subpopulations

African (AFR)

AF:

0.00623

AC:

AN:

8982

American (AMR)

AF:

0.0144

AC:

AN:

2224

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

858

East Asian (EAS)

AF:

0.000502

AC:

AN:

1994

South Asian (SAS)

AF:

0.0117

AC:

AN:

684

European-Finnish (FIN)

AF:

0.0686

AC:

166

AN:

2420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0326

AC:

599

AN:

18392

Other (OTH)

AF:

0.0124

AC:

AN:

404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00864

Hom.:

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Familial prostate cancer

Other:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:association

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.13

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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8-127325027-T-TAC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over