3-56080870-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015576.3(ERC2):c.1588A>G(p.Met530Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ERC2 NM_015576.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33508438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERC2	NM_015576.3	c.1588A>G	p.Met530Val	missense_variant	7/18	ENST00000288221.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERC2	ENST00000288221.11	c.1588A>G	p.Met530Val	missense_variant	7/18	1	NM_015576.3	P1
ERC2	ENST00000460849.5	c.1588A>G	p.Met530Val	missense_variant, NMD_transcript_variant	7/19	1
ERC2	ENST00000492584.3	c.1588A>G	p.Met530Val	missense_variant	7/18	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461490 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727012

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

The c.1588A>G (p.M530V) alteration is located in exon 7 (coding exon 6) of the ERC2 gene. This alteration results from a A to G substitution at nucleotide position 1588, causing the methionine (M) at amino acid position 530 to be replaced by a valine (V). 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	0.58
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.098	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.97	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.30	T;T
Polyphen		0.026	B;B
Vest4		0.59
MutPred		0.65		Loss of ubiquitination at K531 (P = 0.0367);Loss of ubiquitination at K531 (P = 0.0367);
MVP		0.62
MPC		0.37
ClinPred		0.77	D
GERP RS		4.6
Varity_R		0.44
gMVP		0.99

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

Other links and lift over

dbSNP: rs2077196000; hg19: chr3-56114898;