Genetic Variant CASC8:n.547-11725T>C (chr8-127334879-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.547-11725T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,158 control chromosomes in the GnomAD database, including 2,243 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 0.16 ( 2243 hom., cov: 32)

Consequence

CASC8
ENST00000501396.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.779

Publications

2 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=-0.93).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC21	NR_117099.1 link	n.303-4402A>G		intron_variant	Intron 2 of 3
CASC8	NR_117100.1 link	n.1177-44819T>C		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CASC8	ENST00000501396.6 link	n.547-11725T>C	intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5 link	n.1177-44819T>C	intron_variant	Intron 5 of 5	1
CASC8	ENST00000523825.3 link	n.547-44819T>C	intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24453

AN:

152040

Hom.:

2239

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0805

Gnomad AMI

AF:

0.322

Gnomad AMR

AF:

0.213

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.0468

Gnomad SAS

AF:

0.223

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.184

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

GnomAD4 genome

AF:

0.161

AC:

24468

AN:

152158

Hom.:

2243

Cov.:

AF XY:

0.161

AC XY:

11940

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0803

AC:

3335

AN:

41538

American (AMR)

AF:

0.213

AC:

3263

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

678

AN:

3468

East Asian (EAS)

AF:

0.0469

AC:

243

AN:

5176

South Asian (SAS)

AF:

0.224

AC:

1078

AN:

4818

European-Finnish (FIN)

AF:

0.144

AC:

1531

AN:

10596

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.200

AC:

13584

AN:

67962

Other (OTH)

AF:

0.186

AC:

394

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1017

2035

3052

4070

5087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

282

564

846

1128

1410

<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:

0.186

Hom.:

7926

Bravo

AF:

0.162

Asia WGS

AF:

0.148

AC:

515

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.66

(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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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