chr12-15623161-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004447.6(EPS8):​c.2352G>T​(p.Leu784Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L784L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPS8 NM_004447.6 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19384274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6	c.2352G>T	p.Leu784Phe	missense_variant	Exon 20 of 21	ENST00000281172.10	NP_004438.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10	c.2352G>T	p.Leu784Phe	missense_variant	Exon 20 of 21	1	NM_004447.6	ENSP00000281172.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;D;.;D;D;D;D;.;D;D;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.31	N
LIST_S2	Pathogenic	0.98	.;.;.;.;D;.;.;.;.;D;.;D;.;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L;L;.;L;L;L;L;.;L;L;.;.
PhyloP100		-0.49
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D;.;D;.;.;.;.;.;.;.;.;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;.;D;.;.;.;.;.;.;.;.;D;D;D
Sift4G	Uncertain	0.034	D;.;D;.;.;.;.;.;.;.;.;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D;D;D;.;D;D;.;.
Vest4		0.74
MutPred		0.19		Loss of catalytic residue at L784 (P = 0.088);Loss of catalytic residue at L784 (P = 0.088);Loss of catalytic residue at L784 (P = 0.088);Loss of catalytic residue at L784 (P = 0.088);.;Loss of catalytic residue at L784 (P = 0.088);Loss of catalytic residue at L784 (P = 0.088);Loss of catalytic residue at L784 (P = 0.088);Loss of catalytic residue at L784 (P = 0.088);.;Loss of catalytic residue at L784 (P = 0.088);Loss of catalytic residue at L784 (P = 0.088);.;.;
MVP		0.67
MPC		0.55
ClinPred		0.90	D
GERP RS		-0.92
Varity_R		0.30
gMVP		0.54
Mutation Taster		=49/51	disease causing

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;