dbSNP rs16902149: CASC8:n.546+25969C>G (chr8-127394860-G-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+25969C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0837 in 152,150 control chromosomes in the GnomAD database, including 757 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 0.084 ( 756 hom., cov: 32)

Exomes 𝑓: 0.14 ( 1 hom. )

Consequence

CASC8
ENST00000501396.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.522

Publications

4 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=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC8	NR_117100.1 link	n.1176+25969C>G		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CASC8	ENST00000501396.6 link	n.546+25969C>G	intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5 link	n.1176+25969C>G	intron_variant	Intron 5 of 5	1
CASC8	ENST00000523825.3 link	n.546+25969C>G	intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes

AF:

0.0836

AC:

12713

AN:

152010

Hom.:

751

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0403

Gnomad ASJ

AF:

0.0791

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0218

Gnomad FIN

AF:

0.0306

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0632

Gnomad OTH

AF:

0.0752

GnomAD4 exome

AF:

0.136

AC:

AN:

Hom.:

AF XY:

0.0625

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0837

AC:

12737

AN:

152128

Hom.:

756

Cov.:

AF XY:

0.0791

AC XY:

5886

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.166

AC:

6900

AN:

41490

American (AMR)

AF:

0.0401

AC:

613

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0791

AC:

274

AN:

3466

East Asian (EAS)

AF:

0.00271

AC:

AN:

5170

South Asian (SAS)

AF:

0.0216

AC:

104

AN:

4816

European-Finnish (FIN)

AF:

0.0306

AC:

324

AN:

10602

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0632

AC:

4299

AN:

67994

Other (OTH)

AF:

0.0744

AC:

157

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

565

1130

1695

2260

2825

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0787

Hom.:

Bravo

AF:

0.0892

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.1

(source)

DANN

Benign

0.38

PhyloP100

-0.52

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over