chr8-127325027-T-TAC

Variant names:

• chr8-127325027-T-TAC
• rs201361304
• ENST00000501396.6:n.547-1875_547-1874dupGT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000501396.6(CASC8):​n.547-1875_547-1874dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 36,346 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.024 (2 hom., cov: 25)
• Consequence: CASC8 ENST00000501396.6 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.131
• Publications: 0 publications found

Genes affected

CASC8 (HGNC:45129): (cancer susceptibility 8)

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]

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]

CASC21 (HGNC:49836): (cancer susceptibility 21)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0239 (869/36346) while in subpopulation NFE AF = 0.0326 (599/18392). AF 95% confidence interval is 0.0304. There are 2 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC21	NR_117099.1	n.302+2802_302+2803dupAC		intron_variant	Intron 2 of 3
CASC8	NR_117100.1	n.1177-34969_1177-34968dupGT		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASC8	ENST00000501396.6	n.547-1875_547-1874dupGT		intron_variant	Intron 1 of 2	1
CASC8	ENST00000502082.5	n.1177-34969_1177-34968dupGT		intron_variant	Intron 5 of 5	1
CASC8	ENST00000523825.3	n.547-34969_547-34968dupGT		intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 870 AN: 36294 Hom.: 2 Cov.: 25

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.00311

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.000500

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0686

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0126

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

GnomAD4 genome AF: 0.0239 AC: 869 AN: 36346 Hom.: 2 Cov.: 25 AF XY: 0.0248 AC XY: 429 AN XY: 17284

African (AFR) AF: 0.00623 AC: 56 AN: 8982

American (AMR) AF: 0.0144 AC: 32 AN: 2224

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 1 AN: 858

East Asian (EAS) AF: 0.000502 AC: 1 AN: 1994

South Asian (SAS) AF: 0.0117 AC: 8 AN: 684

European-Finnish (FIN) AF: 0.0686 AC: 166 AN: 2420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.0326 AC: 599 AN: 18392

Other (OTH) AF: 0.0124 AC: 5 AN: 404

Alfa AF: 0.00864 Hom.: 1

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial prostate cancer Other:1

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University of Washington Center for Mendelian Genomics, University of Washington

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13

Splicing

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

Other links and lift over

dbSNP: rs201361304; hg19: chr8-128337272;