chr19-16392322-G-C

Position:

• chr19-16392322-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001258374.3(EPS15L1):​c.2085C>G​(p.Asn695Lys) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EPS15L1 NM_001258374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

Genes affected

EPS15L1 (HGNC:24634): (epidermal growth factor receptor pathway substrate 15 like 1) Enables cadherin binding activity. Predicted to be involved in endocytosis and endosomal transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084650606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPS15L1	NM_001258374.3	c.2085C>G	p.Asn695Lys	missense_variant	19/24	ENST00000455140.7	NP_001245303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPS15L1	ENST00000455140.7	c.2085C>G	p.Asn695Lys	missense_variant	19/24	2	NM_001258374.3	ENSP00000393313	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.2085C>G (p.N695K) alteration is located in exon 19 (coding exon 19) of the EPS15L1 gene. This alteration results from a C to G substitution at nucleotide position 2085, causing the asparagine (N) at amino acid position 695 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.56
DEOGEN2	Benign	0.077	.;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N;N;.
REVEL	Benign	0.061
Sift	Benign	0.73	T;T;T;.
Sift4G	Benign	0.37	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.17
MutPred		0.16		Gain of ubiquitination at N695 (P = 0.0022);Gain of ubiquitination at N695 (P = 0.0022);Gain of ubiquitination at N695 (P = 0.0022);.;
MVP		0.30
MPC		0.10
ClinPred		0.20	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.12

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: chr19-16503133;