Genetic Variant CASC8:n.547-10064T>C (chr8-127333218-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.547-10064T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 151,998 control chromosomes in the GnomAD database, including 13,680 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 0.42 ( 13680 hom., cov: 32)

Consequence

CASC8
ENST00000501396.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.784

Publications

14 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC21	NR_117099.1 link	n.303-6063A>G		intron_variant	Intron 2 of 3
CASC8	NR_117100.1 link	n.1177-43158T>C		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CASC8	ENST00000501396.6 link	n.547-10064T>C	intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5 link	n.1177-43158T>C	intron_variant	Intron 5 of 5	1
CASC8	ENST00000523825.3 link	n.547-43158T>C	intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes

AF:

0.420

AC:

63808

AN:

151880

Hom.:

13657

Cov.:

show subpopulations

Gnomad AFR

AF:

0.425

Gnomad AMI

AF:

0.573

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.415

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.492

Gnomad FIN

AF:

0.287

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.403

Gnomad OTH

AF:

0.464

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

GnomAD4 genome

AF:

0.420

AC:

63885

AN:

151998

Hom.:

13680

Cov.:

AF XY:

0.419

AC XY:

31163

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.425

AC:

17601

AN:

41422

American (AMR)

AF:

0.527

AC:

8045

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

1438

AN:

3466

East Asian (EAS)

AF:

0.458

AC:

2371

AN:

5174

South Asian (SAS)

AF:

0.493

AC:

2375

AN:

4818

European-Finnish (FIN)

AF:

0.287

AC:

3037

AN:

10564

Middle Eastern (MID)

AF:

0.517

AC:

152

AN:

294

European-Non Finnish (NFE)

AF:

0.403

AC:

27361

AN:

67970

Other (OTH)

AF:

0.465

AC:

984

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1921

3841

5762

7682

9603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.416

Hom.:

42607

Bravo

AF:

0.439

Asia WGS

AF:

0.476

AC:

1653

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.25

(source)

DANN

Benign

0.54

PhyloP100

-0.78

Splicing

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

Publications

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8-127333218-A-G

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