chr12-1028061-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178040.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERC1	NM_178040.4	MANE Select	c.158C>A	p.Thr53Asn	missense	Exon 2 of 19	NP_829884.1	Q8IUD2-1
	ERC1	NM_178039.4		c.158C>A	p.Thr53Asn	missense	Exon 2 of 18	NP_829883.1	Q8IUD2-3
	ERC1	NM_001301248.1		c.158C>A	p.Thr53Asn	missense	Exon 1 of 19	NP_001288177.1	G8JLD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERC1	ENST00000360905.9	TSL:1 MANE Select	c.158C>A	p.Thr53Asn	missense	Exon 2 of 19	ENSP00000354158.3	Q8IUD2-1
	ERC1	ENST00000589028.6	TSL:1	c.158C>A	p.Thr53Asn	missense	Exon 3 of 20	ENSP00000468263.1	Q8IUD2-1
	ERC1	ENST00000543086.7	TSL:1	c.158C>A	p.Thr53Asn	missense	Exon 2 of 18	ENSP00000438546.1	Q8IUD2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.16		Gain of catalytic residue at S50 (P = 0)
MVP		0.95
MPC		1.2
ClinPred		0.77	D
GERP RS		5.8
PromoterAI		0.016	Neutral
Varity_R		0.33
gMVP		0.80
Mutation Taster		=41/59	disease causing

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: rs1967199681; hg19: chr12-1137227;