Genetic Variant CASC8:n.546+45050T>C (chr8-127375779-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.546+45050T>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 152,086 control chromosomes in the GnomAD database, including 15,046 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 ( 15046 hom., cov: 32)

Consequence

CASC8
ENST00000501396.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0580

Publications

16 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=-0.95).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC21	NR_117099.1 link	n.458-16725A>G		intron_variant	Intron 3 of 3
CASC8	NR_117100.1 link	n.1176+45050T>C		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CASC8	ENST00000501396.6 link	n.546+45050T>C	intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5 link	n.1176+45050T>C	intron_variant	Intron 5 of 5	1
PCAT1	ENST00000521586.2 link	n.290-16725A>G	intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66550

AN:

151968

Hom.:

15042

Cov.:

show subpopulations

Gnomad AFR

AF:

0.544

Gnomad AMI

AF:

0.273

Gnomad AMR

AF:

0.311

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.325

Gnomad FIN

AF:

0.446

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.421

Gnomad OTH

AF:

0.404

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

GnomAD4 genome

AF:

0.438

AC:

66578

AN:

152086

Hom.:

15046

Cov.:

AF XY:

0.432

AC XY:

32071

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.544

AC:

22545

AN:

41460

American (AMR)

AF:

0.311

AC:

4759

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

1733

AN:

3472

East Asian (EAS)

AF:

0.273

AC:

1413

AN:

5182

South Asian (SAS)

AF:

0.325

AC:

1568

AN:

4820

European-Finnish (FIN)

AF:

0.446

AC:

4710

AN:

10554

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.421

AC:

28632

AN:

67978

Other (OTH)

AF:

0.404

AC:

854

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1922

3844

5765

7687

9609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

608

1216

1824

2432

3040

<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:

0.423

Hom.:

24029

Bravo

AF:

0.434

Asia WGS

AF:

0.304

AC:

1058

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

5.3

(source)

DANN

Benign

0.63

PhyloP100

0.058

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