Genetic Variant ENST00000501396.6:n.546+3353A>G (chr8-127417476-T-C) – 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+3353A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 155,558 control chromosomes in the GnomAD database, including 31,557 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 0.63 ( 30791 hom., cov: 31)

Exomes 𝑓: 0.62 ( 766 hom. )

Consequence

CASC8
ENST00000501396.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0360

Publications

5 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:

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=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC8	NR_117100.1 link	n.1176+3353A>G		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CASC8	ENST00000501396.6 link	n.546+3353A>G	intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5 link	n.1176+3353A>G	intron_variant	Intron 5 of 5	1
CASC8	ENST00000523825.3 link	n.546+3353A>G	intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes

AF:

0.633

AC:

95895

AN:

151572

Hom.:

30779

Cov.:

show subpopulations

Gnomad AFR

AF:

0.532

Gnomad AMI

AF:

0.699

Gnomad AMR

AF:

0.702

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.795

Gnomad SAS

AF:

0.668

Gnomad FIN

AF:

0.685

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.655

Gnomad OTH

AF:

0.653

GnomAD4 exome

AF:

0.619

AC:

2394

AN:

3868

Hom.:

766

Cov.:

AF XY:

0.640

AC XY:

1138

AN XY:

1778

show subpopulations

African (AFR)

AF:

0.509

AC:

AN:

106

American (AMR)

AF:

0.648

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

161

AN:

278

East Asian (EAS)

AF:

0.738

AC:

540

AN:

732

South Asian (SAS)

AF:

0.520

AC:

AN:

European-Finnish (FIN)

AF:

0.875

AC:

AN:

Middle Eastern (MID)

AF:

0.773

AC:

AN:

European-Non Finnish (NFE)

AF:

0.588

AC:

1338

AN:

2274

Other (OTH)

AF:

0.626

AC:

194

AN:

310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.632

AC:

95942

AN:

151690

Hom.:

30791

Cov.:

AF XY:

0.640

AC XY:

47410

AN XY:

74124

show subpopulations

African (AFR)

AF:

0.532

AC:

21997

AN:

41382

American (AMR)

AF:

0.702

AC:

10722

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

2133

AN:

3470

East Asian (EAS)

AF:

0.795

AC:

4107

AN:

5168

South Asian (SAS)

AF:

0.666

AC:

3204

AN:

4808

European-Finnish (FIN)

AF:

0.685

AC:

7124

AN:

10402

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.655

AC:

44432

AN:

67878

Other (OTH)

AF:

0.655

AC:

1382

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1741

3482

5222

6963

8704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.646

Hom.:

121892

Bravo

AF:

0.629

Asia WGS

AF:

0.716

AC:

2487

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.8

(source)

DANN

Benign

0.62

PhyloP100

0.036

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over