Genetic Variant ESPNL:p.Arg20Trp (chr2-238100477-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_194312.4(ESPNL):c.58C>T(p.Arg20Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,603,562 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

ESPNL
NM_194312.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.07

Variant links:

Genes affected

ESPNL (HGNC:27937): (espin like) Predicted to enable actin filament binding activity. Predicted to be involved in actin filament bundle assembly and sensory perception of sound. Predicted to be located in stereocilium tip. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ESPNL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03813395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPNL	NM_194312.4 link	c.58C>T	p.Arg20Trp	missense_variant	Exon 1 of 9	ENST00000343063.8	NP_919288.2	Q6ZVH7-1B3KXY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPNL	ENST00000343063.8 link	c.58C>T	p.Arg20Trp	missense_variant	Exon 1 of 9	2	NM_194312.4	ENSP00000339115.3		Q6ZVH7-1
ESPNL	ENST00000409169.5 link	c.58C>T	p.Arg20Trp	missense_variant	Exon 1 of 8	5		ENSP00000386577.1		Q6ZVH7-2

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000395

AC:

AN:

220138

Hom.:

AF XY:

0.000355

AC XY:

AN XY:

121002

show subpopulations

Gnomad AFR exome

AF:

0.000153

Gnomad AMR exome

AF:

0.000185

Gnomad ASJ exome

AF:

0.000109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000352

Gnomad FIN exome

AF:

0.00145

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.000187

GnomAD4 exome

AF:

0.000289

AC:

420

AN:

1451208

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

205

AN XY:

721204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000903

Gnomad4 AMR exome

AF:

0.000138

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000142

Gnomad4 FIN exome

AF:

0.00121

Gnomad4 NFE exome

AF:

0.000292

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000269

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00103

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000187

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000350

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58C>T (p.R20W) alteration is located in exon 1 (coding exon 1) of the ESPNL gene. This alteration results from a C to T substitution at nucleotide position 58, causing the arginine (R) at amino acid position 20 to be replaced by a tryptophan (W). 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

0.092

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

0.021

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.43

N;N

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.26

Sift

Benign

0.26

T;T

Sift4G

Uncertain

0.012

D;D

Polyphen

1.0

D;.

Vest4

0.34

MVP

0.52

MPC

0.51

ClinPred

0.12

GERP RS

4.4

Varity_R

0.14

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over