Genetic Variant CASC8:n.547-20218T>C (chr8-127343372-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000501396.6(CASC8):n.547-20218T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 151,744 control chromosomes in the GnomAD database, including 14,807 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.44 ( 14807 hom., cov: 30)

Consequence

CASC8
ENST00000501396.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.563

Publications

280 publications found

Variant links:

Genes affected

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

CASC8 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:

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:

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

CASC21 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC21	NR_117099.1 link	n.457+3937A>G		intron_variant	Intron 3 of 3
CASC8	NR_117100.1 link	n.1177-53312T>C		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CASC8	ENST00000501396.6 link	n.547-20218T>C	intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5 link	n.1177-53312T>C	intron_variant	Intron 5 of 5	1
PCAT1	ENST00000521586.2 link	n.289+3937A>G	intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66397

AN:

151624

Hom.:

14769

Cov.:

show subpopulations

Gnomad AFR

AF:

0.440

Gnomad AMI

AF:

0.570

Gnomad AMR

AF:

0.537

Gnomad ASJ

AF:

0.440

Gnomad EAS

AF:

0.512

Gnomad SAS

AF:

0.511

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.532

Gnomad NFE

AF:

0.414

Gnomad OTH

AF:

0.476

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

GnomAD4 genome

AF:

0.438

AC:

66487

AN:

151744

Hom.:

14807

Cov.:

AF XY:

0.438

AC XY:

32474

AN XY:

74144

show subpopulations

African (AFR)

AF:

0.441

AC:

18230

AN:

41384

American (AMR)

AF:

0.537

AC:

8182

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.440

AC:

1521

AN:

3460

East Asian (EAS)

AF:

0.512

AC:

2634

AN:

5146

South Asian (SAS)

AF:

0.512

AC:

2465

AN:

4814

European-Finnish (FIN)

AF:

0.345

AC:

3623

AN:

10494

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.414

AC:

28141

AN:

67896

Other (OTH)

AF:

0.480

AC:

1012

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1875

3750

5626

7501

9376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.424

Hom.:

44349

Bravo

AF:

0.452

Asia WGS

AF:

0.525

AC:

1823

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.0

(source)

DANN

Benign

0.48

PhyloP100

0.56

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over