12-15863174-T-C

Variant names:

• chr12-15863174-T-C
• rs10846239
• ENST00000646828.1:c.-336+17933A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000646828.1(EPS8):​c.-336+17933A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 152,154 control chromosomes in the GnomAD database, including 30,037 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 0.57 (30037 hom., cov: 33)
• Consequence: EPS8 ENST00000646828.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279
• Publications: 4 publications found

Genes affected

EPS8 (HGNC:3420): (EGFR pathway substrate 8, signaling adaptor) This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

EPS8 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 102

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC102724146 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC102724146	XR_002957404.2	n.130-17734A>G		intron_variant	Intron 2 of 6
LOC102724146	XR_007063227.1	n.613-17734A>G		intron_variant	Intron 2 of 3
LOC102724146	XR_007063228.1	n.129+17933A>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000646828.1	c.-336+17933A>G		intron_variant	Intron 1 of 23			ENSP00000494842.1
EPS8	ENST00000646918.1	c.-366+17933A>G		intron_variant	Intron 2 of 23			ENSP00000495722.1
EPS8	ENST00000647087.1	c.-174+17933A>G		intron_variant	Intron 2 of 22			ENSP00000496406.1
EPS8	ENST00000535752.5	c.-22+17933A>G		intron_variant	Intron 2 of 5	4		ENSP00000440591.1

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86787 AN: 152036 Hom.: 30043 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.691

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.589

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

GnomAD4 genome AF: 0.570 AC: 86776 AN: 152154 Hom.: 30037 Cov.: 33 AF XY: 0.574 AC XY: 42688 AN XY: 74380

African (AFR) AF: 0.155 AC: 6431 AN: 41508

American (AMR) AF: 0.612 AC: 9350 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2351 AN: 3472

East Asian (EAS) AF: 0.768 AC: 3987 AN: 5190

South Asian (SAS) AF: 0.805 AC: 3886 AN: 4830

European-Finnish (FIN) AF: 0.711 AC: 7518 AN: 10576

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.753 AC: 51178 AN: 67988

Other (OTH) AF: 0.591 AC: 1248 AN: 2110

Alfa AF: 0.693 Hom.: 24004

Bravo AF: 0.542

Asia WGS AF: 0.751 AC: 2613 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	8.6
DANN	Benign	0.60
PhyloP100		0.28

Splicing

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

Other links and lift over

dbSNP: rs10846239; hg19: chr12-16016108;