3-55888428-A-G

Variant names:

• chr3-55888428-A-G
• rs200582069
• NM_015576.3:c.2525T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015576.3(ERC2):​c.2525T>C​(p.Ile842Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,668 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I842S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: ERC2 NM_015576.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012260675).
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERC2	NM_015576.3	c.2525T>C	p.Ile842Thr	missense_variant	Exon 14 of 18	ENST00000288221.11	NP_056391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERC2	ENST00000288221.11	c.2525T>C	p.Ile842Thr	missense_variant	Exon 14 of 18	1	NM_015576.3	ENSP00000288221.6
ERC2	ENST00000460849.5	n.2525T>C		non_coding_transcript_exon_variant	Exon 14 of 19	1		ENSP00000417445.1
ERC2	ENST00000492584.3	c.2549T>C	p.Ile850Thr	missense_variant	Exon 14 of 18	5		ENSP00000417280.3

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152034 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000317 AC: 79 AN: 249134 AF XY: 0.000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1461634 Hom.: 1 Cov.: 30 AF XY: 0.000151 AC XY: 110 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00589 AC: 154 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111822

Other (OTH) AF: 0.000447 AC: 27 AN: 60370

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000341 Hom.: 1

Bravo AF: 0.000223

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000223 AC: 27

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2525T>C (p.I842T) alteration is located in exon 14 (coding exon 13) of the ERC2 gene. This alteration results from a T to C substitution at nucleotide position 2525, causing the isoleucine (I) at amino acid position 842 to be replaced by a threonine (T). 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	0.069
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.027	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
PhyloP100		3.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.96	N;.
REVEL	Benign	0.23
Sift	Benign	0.081	T;.
Sift4G	Benign	0.48	T;T
Polyphen		0.0020	B;B
Vest4		0.28
MVP		0.97
MPC		0.46
ClinPred		0.031	T
GERP RS		4.6
Varity_R		0.064
gMVP		0.17
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs200582069; hg19: chr3-55922456;