16-10547539-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP3_Moderate
The NM_001424.6(EMP2):c.78+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000205 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
EMP2
NM_001424.6 splice_donor
NM_001424.6 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.51
Genes affected
EMP2 (HGNC:3334): (epithelial membrane protein 2) This gene encodes a tetraspan protein of the PMP22/EMP family. The encoded protein regulates cell membrane composition. It has been associated with various functions including endocytosis, cell signaling, cell proliferation, cell migration, cell adhesion, cell death, cholesterol homeostasis, urinary albumin excretion, and embryo implantation. It is known to negatively regulate caveolin-1, a scaffolding protein which is the main component of the caveolae plasma membrane invaginations found in most cell types. Through activation of PTK2 it positively regulates vascular endothelial growth factor A. It also modulates the function of specific integrin isomers in the plasma membrane. Up-regulation of this gene has been linked to cancer progression in multiple different tissues. Mutations in this gene have been associated with nephrotic syndrome type 10 (NPHS10). [provided by RefSeq, Mar 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2718254 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.264
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EMP2 | NM_001424.6 | c.78+1G>A | splice_donor_variant | ENST00000359543.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EMP2 | ENST00000359543.8 | c.78+1G>A | splice_donor_variant | 1 | NM_001424.6 | P1 | |||
EMP2 | ENST00000536829.1 | c.78+1G>A | splice_donor_variant | 2 | P1 | ||||
EMP2 | ENST00000342147.4 | n.223G>A | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461698Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727116
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1461698
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30
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0
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727116
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at