4-100421284-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_016242.4(EMCN):​c.662C>T​(p.Pro221Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000116 in 1,459,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

EMCN
NM_016242.4 missense, splice_region

Scores

5
6
8
Splicing: ADA: 0.9981
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.55
Variant links:
Genes affected
EMCN (HGNC:16041): (endomucin) EMCN is a mucin-like sialoglycoprotein that interferes with the assembly of focal adhesion complexes and inhibits interaction between cells and the extracellular matrix (Kinoshita et al., 2001 [PubMed 11418125]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EMCNNM_016242.4 linkc.662C>T p.Pro221Leu missense_variant, splice_region_variant 8/12 ENST00000296420.9 NP_057326.2 Q9ULC0-1Q4W5J1
EMCNNM_001159694.2 linkc.623C>T p.Pro208Leu missense_variant, splice_region_variant 7/11 NP_001153166.1 Q9ULC0-3
EMCNXM_011532024.4 linkc.662C>T p.Pro221Leu missense_variant, splice_region_variant 8/12 XP_011530326.1 Q9ULC0-1Q4W5J1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EMCNENST00000296420.9 linkc.662C>T p.Pro221Leu missense_variant, splice_region_variant 8/121 NM_016242.4 ENSP00000296420.4 Q9ULC0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000518
AC:
13
AN:
250742
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135542
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000349
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1459902
Hom.:
0
Cov.:
30
AF XY:
0.00000826
AC XY:
6
AN XY:
726296
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000269
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000264
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000577
AC:
7

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 27, 2024The c.662C>T (p.P221L) alteration is located in exon 8 (coding exon 8) of the EMCN gene. This alteration results from a C to T substitution at nucleotide position 662, causing the proline (P) at amino acid position 221 to be replaced by a leucine (L). 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
0.28
BayesDel_addAF
Benign
-0.012
T
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.016
T
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
1.0
L;.
PrimateAI
Benign
0.46
T
PROVEAN
Pathogenic
-8.8
D;D
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.68
MutPred
0.69
Loss of disorder (P = 0.0126);.;
MVP
0.095
MPC
0.057
ClinPred
0.55
D
GERP RS
5.4
Varity_R
0.60
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.89
SpliceAI score (max)
0.14
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: rs777232534; hg19: chr4-101342441; API