Variant 3-55888391-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015576.3(ERC2):c.2562G>A(p.Met854Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ERC2
NM_015576.3 missense, splice_region

Scores

Splicing: ADA: 0.9498

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

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]

ERC2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERC2	NM_015576.3 linkuse as main transcript	c.2562G>A	p.Met854Ile	missense_variant, splice_region_variant	14/18	ENST00000288221.11	NP_056391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ERC2	ENST00000288221.11 linkuse as main transcript	c.2562G>A	p.Met854Ile	missense_variant, splice_region_variant	14/18	1	NM_015576.3	ENSP00000288221	P1
ERC2	ENST00000460849.5 linkuse as main transcript	c.2562G>A	p.Met854Ile	missense_variant, splice_region_variant, NMD_transcript_variant	14/19	1		ENSP00000417445
ERC2	ENST00000492584.3 linkuse as main transcript	c.2586G>A	p.Met862Ile	missense_variant, splice_region_variant	14/18	5		ENSP00000417280

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248926

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135046

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461544

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

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 submitter

clinical testing

Ambry Genetics

Apr 04, 2024

The c.2562G>A (p.M854I) alteration is located in exon 14 (coding exon 13) of the ERC2 gene. This alteration results from a G to A substitution at nucleotide position 2562, causing the methionine (M) at amino acid position 854 to be replaced by an isoleucine (I). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.4

N;.

REVEL

Benign

0.23

Sift

Uncertain

0.010

D;.

Sift4G

Uncertain

0.033

D;D

Polyphen

0.70

P;P

Vest4

0.78

MutPred

0.52

Gain of catalytic residue at L859 (P = 0.0634);Gain of catalytic residue at L859 (P = 0.0634);

MVP

0.39

MPC

1.1

ClinPred

0.96

GERP RS

5.8

Varity_R

0.48

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Pathogenic

0.80

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