rs12814229

Variant names:

• chr12-15622852-C-A
• rs12814229
• NM_004447.6:c.2355+306G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-15622852-C-A
• chr12-15622852-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004447.6(EPS8):​c.2355+306G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 151,686 control chromosomes in the GnomAD database, including 1,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1928 hom., cov: 32)
• Consequence: EPS8 NM_004447.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.373
• Publications: 2 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-15622852-C-A is Benign according to our data. Variant chr12-15622852-C-A is described in ClinVar as Benign. ClinVar VariationId is 1221592.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004447.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	NM_004447.6	MANE Select	c.2355+306G>T		intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.2391+306G>T		intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.2355+306G>T		intron	N/A	NP_001400761.1	Q12929-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	ENST00000281172.10	TSL:1 MANE Select	c.2355+306G>T		intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.*1615+306G>T		intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.2430+306G>T		intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21257 AN: 151596 Hom.: 1935 Cov.: 32

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.140 AC: 21241 AN: 151686 Hom.: 1928 Cov.: 32 AF XY: 0.143 AC XY: 10564 AN XY: 74080

African (AFR) AF: 0.0415 AC: 1716 AN: 41382

American (AMR) AF: 0.145 AC: 2207 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 952 AN: 3462

East Asian (EAS) AF: 0.227 AC: 1174 AN: 5162

South Asian (SAS) AF: 0.165 AC: 795 AN: 4810

European-Finnish (FIN) AF: 0.190 AC: 1979 AN: 10402

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.174 AC: 11853 AN: 67926

Other (OTH) AF: 0.177 AC: 374 AN: 2108

Alfa AF: 0.137 Hom.: 609

Bravo AF: 0.135

Asia WGS AF: 0.171 AC: 593 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.78
DANN	Benign	0.40
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12814229; hg19: chr12-15775786;