chr3-56139656-T-G

Position:

• chr3-56139656-T-G

Variant summary

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

The NM_015576.3(ERC2):​c.1326A>C​(p.Glu442Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERC2 NM_015576.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.474

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=0.36829004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERC2	NM_015576.3	c.1326A>C	p.Glu442Asp	missense_variant	6/18	ENST00000288221.11	NP_056391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERC2	ENST00000288221.11	c.1326A>C	p.Glu442Asp	missense_variant	6/18	1	NM_015576.3	ENSP00000288221	P1
ERC2	ENST00000460849.5	c.1326A>C	p.Glu442Asp	missense_variant, NMD_transcript_variant	6/19	1		ENSP00000417445
ERC2	ENST00000492584.3	c.1326A>C	p.Glu442Asp	missense_variant	6/18	5		ENSP00000417280

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 23, 2024

The c.1326A>C (p.E442D) alteration is located in exon 6 (coding exon 5) of the ERC2 gene. This alteration results from a A to C substitution at nucleotide position 1326, causing the glutamic acid (E) at amino acid position 442 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.054
Eigen_PC	Benign	0.0039
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;N
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.26
Sift	Benign	0.18	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.98	D;D
Vest4		0.41
MutPred		0.48		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.37
MPC		0.34
ClinPred		0.53	D
GERP RS		2.1
Varity_R		0.18
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-56173684;