2-238102061-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_194312.4(ESPNL):​c.415C>T​(p.Arg139Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,593,290 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ESPNL
NM_194312.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.664
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.12729362).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ESPNLNM_194312.4 linkc.415C>T p.Arg139Trp missense_variant Exon 2 of 9 ENST00000343063.8 NP_919288.2 Q6ZVH7-1B3KXY4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ESPNLENST00000343063.8 linkc.415C>T p.Arg139Trp missense_variant Exon 2 of 9 2 NM_194312.4 ENSP00000339115.3 Q6ZVH7-1
ESPNLENST00000409169.5 linkc.415C>T p.Arg139Trp missense_variant Exon 2 of 8 5 ENSP00000386577.1 Q6ZVH7-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000286
AC:
6
AN:
209696
Hom.:
0
AF XY:
0.0000260
AC XY:
3
AN XY:
115270
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000320
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000109
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000187
AC:
27
AN:
1441108
Hom.:
0
Cov.:
46
AF XY:
0.0000237
AC XY:
17
AN XY:
715842
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000104
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000208
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000838
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.415C>T (p.R139W) alteration is located in exon 2 (coding exon 2) of the ESPNL gene. This alteration results from a C to T substitution at nucleotide position 415, causing the arginine (R) at amino acid position 139 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
0.081
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0028
T;.
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.90
FATHMM_MKL
Benign
0.047
N
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.051
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.8
L;L
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.45
N;N
REVEL
Benign
0.16
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
0.81
P;.
Vest4
0.33
MutPred
0.57
Loss of disorder (P = 0.0071);Loss of disorder (P = 0.0071);
MVP
0.16
MPC
0.12
ClinPred
0.39
T
GERP RS
-4.3
Varity_R
0.23
gMVP
0.36

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.

Other links and lift over

dbSNP: rs778625183; hg19: chr2-239010702; API