3-56296027-G-T

Variant summary

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

The NM_015576.3(ERC2):c.1066C>A(p.Leu356Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERC2 NM_015576.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERC2	NM_015576.3	c.1066C>A	p.Leu356Ile	missense_variant	3/18	ENST00000288221.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERC2	ENST00000288221.11	c.1066C>A	p.Leu356Ile	missense_variant	3/18	1	NM_015576.3	P1
ERC2	ENST00000460849.5	c.1066C>A	p.Leu356Ile	missense_variant, NMD_transcript_variant	3/19	1
ERC2	ENST00000492584.3	c.1066C>A	p.Leu356Ile	missense_variant	3/18	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Apr 22, 2022

The c.1066C>A (p.L356I) alteration is located in exon 3 (coding exon 2) of the ERC2 gene. This alteration results from a C to A substitution at nucleotide position 1066, causing the leucine (L) at amino acid position 356 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.081	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.77	N;.
REVEL	Benign	0.20
Sift	Benign	0.15	T;.
Sift4G	Benign	0.49	T;T
Polyphen		0.98	D;D
Vest4		0.73
MutPred		0.55		Gain of methylation at K351 (P = 0.0561);Gain of methylation at K351 (P = 0.0561);
MVP		0.42
MPC		0.94
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr3-56330055;