NM_004447.6:c.2352G>A

Variant names:

• chr12-15623161-C-T
• rs1126786
• NM_004447.6:c.2352G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004447.6(EPS8):​c.2352G>A​(p.Leu784Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,604,462 control chromosomes in the GnomAD database, including 10,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L784L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (5081 hom., cov: 32)
  • Exomes 𝑓: 0.038 (5150 hom.)
• Consequence: EPS8 NM_004447.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.489
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-15623161-C-T is Benign according to our data. Variant chr12-15623161-C-T is described in ClinVar as Benign. ClinVar VariationId is 508137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 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.2352G>A	p.Leu784Leu	synonymous	Exon 20 of 21	NP_004438.3
	EPS8	NM_001413831.1		c.2388G>A	p.Leu796Leu	synonymous	Exon 21 of 22	NP_001400760.1
	EPS8	NM_001413832.1		c.2352G>A	p.Leu784Leu	synonymous	Exon 21 of 22	NP_001400761.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	ENST00000281172.10	TSL:1 MANE Select	c.2352G>A	p.Leu784Leu	synonymous	Exon 20 of 21	ENSP00000281172.5
	EPS8	ENST00000543468.5	TSL:1	n.*1612G>A		non_coding_transcript_exon	Exon 19 of 20	ENSP00000445985.1
	EPS8	ENST00000543468.5	TSL:1	n.*1612G>A		3_prime_UTR	Exon 19 of 20	ENSP00000445985.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23361 AN: 151970 Hom.: 5072 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0655

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0415

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.0578 AC: 13963 AN: 241568 AF XY: 0.0493

Gnomad AFR exome AF: 0.495

Gnomad AMR exome AF: 0.0316

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.0433

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0355

GnomAD4 exome AF: 0.0376 AC: 54669 AN: 1452376 Hom.: 5150 Cov.: 31 AF XY: 0.0360 AC XY: 26017 AN XY: 722048

African (AFR) AF: 0.512 AC: 16777 AN: 32742

American (AMR) AF: 0.0352 AC: 1500 AN: 42638

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 613 AN: 25764

East Asian (EAS) AF: 0.0354 AC: 1401 AN: 39606

South Asian (SAS) AF: 0.0452 AC: 3774 AN: 83474

European-Finnish (FIN) AF: 0.00503 AC: 268 AN: 53294

Middle Eastern (MID) AF: 0.0606 AC: 346 AN: 5710

European-Non Finnish (NFE) AF: 0.0241 AC: 26786 AN: 1109170

Other (OTH) AF: 0.0534 AC: 3204 AN: 59978

GnomAD4 genome AF: 0.154 AC: 23404 AN: 152086 Hom.: 5081 Cov.: 32 AF XY: 0.148 AC XY: 11020 AN XY: 74342

African (AFR) AF: 0.485 AC: 20095 AN: 41414

American (AMR) AF: 0.0652 AC: 997 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.0414 AC: 214 AN: 5170

South Asian (SAS) AF: 0.0458 AC: 221 AN: 4828

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10594

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1510 AN: 67998

Other (OTH) AF: 0.114 AC: 241 AN: 2110

Alfa AF: 0.0727 Hom.: 1318

Bravo AF: 0.173

Asia WGS AF: 0.0640 AC: 225 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0256

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.7
DANN	Benign	0.69
PhyloP100		-0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs1126786; hg19: chr12-15776095; COSMIC: COSV55531114; COSMIC: COSV55531114;