12-15624275-G-C

Variant names:

• chr12-15624275-G-C
• NM_004447.6:c.2177C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004447.6(EPS8):​c.2177C>G​(p.Thr726Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPS8 NM_004447.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27544993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6	c.2177C>G	p.Thr726Arg	missense_variant	Exon 19 of 21	ENST00000281172.10	NP_004438.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10	c.2177C>G	p.Thr726Arg	missense_variant	Exon 19 of 21	1	NM_004447.6	ENSP00000281172.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.35	T;T;T;T;.;T;T;T;T;.;T;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.042
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	.;.;.;.;T;.;.;.;.;T;.;T;.;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;.;L;L;L;L;.;L;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;.;N;.;.;.;.;.;.;.;.;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.17	T;.;T;.;.;.;.;.;.;.;.;T;T;T
Sift4G	Benign	0.11	T;.;T;.;.;.;.;.;.;.;.;T;T;T
Polyphen		0.010	B;B;B;B;.;B;B;B;B;.;B;B;.;.
Vest4		0.35
MutPred		0.32		Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);.;Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);.;Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);.;.;
MVP		0.27
MPC		0.18
ClinPred		0.66	D
GERP RS		5.4
Varity_R		0.13
gMVP		0.65

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-15777209;