chr12-1028061-C-A

Variant names:

• chr12-1028061-C-A
• rs1967199681
• NM_178040.4:c.158C>A

Variant summary

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

The NM_178040.4(ERC1):​c.158C>A​(p.Thr53Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERC1 NM_178040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

Genes affected

ERC1 (HGNC:17072): (ELKS/RAB6-interacting/CAST family member 1) The protein encoded by this gene is a member of a family of RIM-binding proteins. RIMs are active zone proteins that regulate neurotransmitter release. This gene has been found fused to the receptor-type tyrosine kinase gene RET by gene rearrangement due to the translocation t(10;12)(q11;p13) in thyroid papillary carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

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 rank	MANE	Protein	UniProt
ERC1	NM_178040.4	c.158C>A	p.Thr53Asn	missense_variant	Exon 2 of 19	ENST00000360905.9	NP_829884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERC1	ENST00000360905.9	c.158C>A	p.Thr53Asn	missense_variant	Exon 2 of 19	1	NM_178040.4	ENSP00000354158.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.158C>A (p.T53N) alteration is located in exon 1 (coding exon 1) of the ERC1 gene. This alteration results from a C to A substitution at nucleotide position 158, causing the threonine (T) at amino acid position 53 to be replaced by an asparagine (N). 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	0.73
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	.;.;.;T;.;.;.;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.1	.;L;.;L;.;L;L;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	.;N;N;N;.;.;N;.;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	.;D;D;D;.;.;D;.;D
Sift4G	Pathogenic	0.0	D;T;T;T;D;T;T;T;T
Polyphen		1.0	.;D;.;D;.;.;D;D;.
Vest4		0.82, 0.84, 0.83, 0.87, 0.81, 0.83, 0.86
MutPred		0.16		Gain of catalytic residue at S50 (P = 0);Gain of catalytic residue at S50 (P = 0);Gain of catalytic residue at S50 (P = 0);Gain of catalytic residue at S50 (P = 0);Gain of catalytic residue at S50 (P = 0);Gain of catalytic residue at S50 (P = 0);Gain of catalytic residue at S50 (P = 0);Gain of catalytic residue at S50 (P = 0);Gain of catalytic residue at S50 (P = 0);
MVP		0.95
MPC		1.2
ClinPred		0.77	D
GERP RS		5.8
Varity_R		0.33
gMVP		0.80

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: rs1967199681; hg19: chr12-1137227;