6-91688947-T-C

Variant names:

• chr6-91688947-T-C
• rs479292
• ENST00000437768.1:n.118+1364A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000437768.1(CASC6):​n.118+1364A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,004 control chromosomes in the GnomAD database, including 4,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency: Genomes: 𝑓 0.22 (4600 hom., cov: 32)
• Consequence: CASC6 ENST00000437768.1 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.226

Genes affected

CASC6 (HGNC:49076): (cancer susceptibility 6)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC6	NR_104154.1	n.118+1364A>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASC6	ENST00000437768.1	n.118+1364A>G		intron_variant	Intron 1 of 3	1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32684 AN: 151888 Hom.: 4581 Cov.: 32

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.215 AC: 32746 AN: 152004 Hom.: 4600 Cov.: 32 AF XY: 0.215 AC XY: 15983 AN XY: 74330

Gnomad4 AFR AF: 0.397

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.196

Alfa AF: 0.183 Hom.: 437

Bravo AF: 0.234

Asia WGS AF: 0.217 AC: 752 AN: 3474

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Letrozole response Other:1

May 01, 2023

Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

This variant has been evaluated in 886 european women with hormone receptor-positive, early-stage breast cancer treated with adjuvant hormone therapy with letrozole. The minor T allele was found to be associated with 1) increased cumulative incidence of distant metastasis, 2) decreased overall survival, 3) descreased cumulative incidence of bone fractures (which is a letrozole-related adverse event) likely associated with decreased letrozole efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.4
DANN	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs479292; hg19: chr6-92398665;