3-55888506-A-T

Position:

• chr3-55888506-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015576.3(ERC2):​c.2447T>A​(p.Leu816Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ERC2 NM_015576.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERC2	NM_015576.3	c.2447T>A	p.Leu816Gln	missense_variant	14/18	ENST00000288221.11	NP_056391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERC2	ENST00000288221.11	c.2447T>A	p.Leu816Gln	missense_variant	14/18	1	NM_015576.3	ENSP00000288221	P1
ERC2	ENST00000460849.5	c.2447T>A	p.Leu816Gln	missense_variant, NMD_transcript_variant	14/19	1		ENSP00000417445
ERC2	ENST00000492584.3	c.2471T>A	p.Leu824Gln	missense_variant	14/18	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

Jun 10, 2024

The c.2447T>A (p.L816Q) alteration is located in exon 14 (coding exon 13) of the ERC2 gene. This alteration results from a T to A substitution at nucleotide position 2447, causing the leucine (L) at amino acid position 816 to be replaced by a glutamine (Q). 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	0.89
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.083	T;T
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.71		Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);
MVP		0.41
MPC		1.1
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.79
gMVP		0.77

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: chr3-55922534;