3-55992067-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_015576.3(ERC2):​c.2245G>A​(p.Glu749Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ERC2
NM_015576.3 missense

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Publications

0 publications found
Variant links:
Genes affected
ERC2 (HGNC:31922): (ELKS/RAB6-interacting/CAST family member 2) This gene encodes a protein that belongs to the Rab3-interacting molecule (RIM)-binding protein family. Members of this protein family form part of the cytomatrix at the active zone (CAZ) complex and function as regulators of neurotransmitter release. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERC2NM_015576.3 linkc.2245G>A p.Glu749Lys missense_variant Exon 11 of 18 ENST00000288221.11 NP_056391.1 O15083

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERC2ENST00000288221.11 linkc.2245G>A p.Glu749Lys missense_variant Exon 11 of 18 1 NM_015576.3 ENSP00000288221.6 O15083
ERC2ENST00000460849.5 linkn.2245G>A non_coding_transcript_exon_variant Exon 11 of 19 1 ENSP00000417445.1 O15083
ERC2ENST00000492584.3 linkc.2281G>A p.Glu761Lys missense_variant Exon 12 of 18 5 ENSP00000417280.3 H7C4G9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460884
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726690
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33416
American (AMR)
AF:
0.00
AC:
0
AN:
44598
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26094
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39686
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86074
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53396
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5750
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111522
Other (OTH)
AF:
0.00
AC:
0
AN:
60348
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 02, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2245G>A (p.E749K) alteration is located in exon 11 (coding exon 10) of the ERC2 gene. This alteration results from a G to A substitution at nucleotide position 2245, causing the glutamic acid (E) at amino acid position 749 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
Uncertain
0.45
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D
M_CAP
Benign
0.037
D
MetaRNN
Pathogenic
0.79
D;D
MetaSVM
Benign
-0.56
T
MutationAssessor
Uncertain
2.6
M;M
PhyloP100
7.9
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-2.9
D;.
REVEL
Uncertain
0.33
Sift
Uncertain
0.0050
D;.
Sift4G
Benign
0.066
T;T
Polyphen
0.98
D;D
Vest4
0.90
MutPred
0.48
Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);
MVP
0.41
MPC
0.88
ClinPred
0.98
D
GERP RS
5.8
Varity_R
0.53
gMVP
0.80
Mutation Taster
=81/19
polymorphism

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

Other links and lift over

hg19: chr3-56026095; API