Genetic Variant CASC8:n.546+30121G>A (chr8-127390708-C-T) – 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+30121G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.88 in 152,208 control chromosomes in the GnomAD database, including 59,080 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 0.88 ( 59080 hom., cov: 32)

Consequence

CASC8
ENST00000501396.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.582

Publications

4 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=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC21	NR_117099.1 link	n.458-1796C>T		intron_variant	Intron 3 of 3
CASC8	NR_117100.1 link	n.1176+30121G>A		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CASC8	ENST00000501396.6 link	n.546+30121G>A	intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5 link	n.1176+30121G>A	intron_variant	Intron 5 of 5	1
PCAT1	ENST00000521586.2 link	n.290-1796C>T	intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes

AF:

0.880

AC:

133891

AN:

152090

Hom.:

59039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.909

Gnomad AMI

AF:

0.889

Gnomad AMR

AF:

0.814

Gnomad ASJ

AF:

0.928

Gnomad EAS

AF:

0.868

Gnomad SAS

AF:

0.848

Gnomad FIN

AF:

0.923

Gnomad MID

AF:

0.869

Gnomad NFE

AF:

0.872

Gnomad OTH

AF:

0.861

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

GnomAD4 genome

AF:

0.880

AC:

133991

AN:

152208

Hom.:

59080

Cov.:

AF XY:

0.882

AC XY:

65580

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.909

AC:

37767

AN:

41528

American (AMR)

AF:

0.814

AC:

12447

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.928

AC:

3223

AN:

3472

East Asian (EAS)

AF:

0.868

AC:

4491

AN:

5176

South Asian (SAS)

AF:

0.848

AC:

4085

AN:

4820

European-Finnish (FIN)

AF:

0.923

AC:

9774

AN:

10592

Middle Eastern (MID)

AF:

0.860

AC:

251

AN:

292

European-Non Finnish (NFE)

AF:

0.872

AC:

59325

AN:

68022

Other (OTH)

AF:

0.862

AC:

1819

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

826

1652

2477

3303

4129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.861

Hom.:

15757

Bravo

AF:

0.869

Asia WGS

AF:

0.847

AC:

2945

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.47

(source)

DANN

Benign

0.24

PhyloP100

-0.58

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