12-1028051-A-G

Variant names:

• chr12-1028051-A-G
• rs35037408
• NM_178040.4:c.148A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_178040.4(ERC1):​c.148A>G​(p.Ser50Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,614,182 control chromosomes in the GnomAD database, including 1,110 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (81 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1029 hom.)
• Consequence: ERC1 NM_178040.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.96
• Publications: 15 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029384196).
• BP6: Variant 12-1028051-A-G is Benign according to our data. Variant chr12-1028051-A-G is described in ClinVar as Benign. ClinVar VariationId is 3037380.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

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.148A>G	p.Ser50Gly	missense	Exon 2 of 19	NP_829884.1	Q8IUD2-1
	ERC1	NM_178039.4		c.148A>G	p.Ser50Gly	missense	Exon 2 of 18	NP_829883.1	Q8IUD2-3
	ERC1	NM_001301248.1		c.148A>G	p.Ser50Gly	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.148A>G	p.Ser50Gly	missense	Exon 2 of 19	ENSP00000354158.3	Q8IUD2-1
	ERC1	ENST00000589028.6	TSL:1	c.148A>G	p.Ser50Gly	missense	Exon 3 of 20	ENSP00000468263.1	Q8IUD2-1
	ERC1	ENST00000543086.7	TSL:1	c.148A>G	p.Ser50Gly	missense	Exon 2 of 18	ENSP00000438546.1	Q8IUD2-3

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3984 AN: 152188 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.00671

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0595

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0273 AC: 6874 AN: 251456 AF XY: 0.0275

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0634

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00781

Gnomad NFE exome AF: 0.0385

Gnomad OTH exome AF: 0.0411

GnomAD4 exome AF: 0.0347 AC: 50687 AN: 1461876 Hom.: 1029 Cov.: 32 AF XY: 0.0343 AC XY: 24971 AN XY: 727234

African (AFR) AF: 0.00568 AC: 190 AN: 33480

American (AMR) AF: 0.0250 AC: 1119 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0673 AC: 1758 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0170 AC: 1468 AN: 86258

European-Finnish (FIN) AF: 0.0101 AC: 538 AN: 53414

Middle Eastern (MID) AF: 0.0674 AC: 389 AN: 5768

European-Non Finnish (NFE) AF: 0.0388 AC: 43109 AN: 1112000

Other (OTH) AF: 0.0350 AC: 2114 AN: 60396

GnomAD4 genome AF: 0.0261 AC: 3977 AN: 152306 Hom.: 81 Cov.: 32 AF XY: 0.0244 AC XY: 1819 AN XY: 74476

African (AFR) AF: 0.00669 AC: 278 AN: 41570

American (AMR) AF: 0.0342 AC: 523 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0595 AC: 206 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0128 AC: 62 AN: 4828

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10624

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0394 AC: 2679 AN: 68022

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0352 Hom.: 288

Bravo AF: 0.0289

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0475 AC: 183

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.0428 AC: 368

ExAC AF: 0.0269 AC: 3261

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0437

EpiControl AF: 0.0429

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ERC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.77	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.28
Sift	Benign	0.33	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.086
MPC		0.30
ClinPred		0.0017	T
GERP RS		-0.43
PromoterAI		-0.0065	Neutral
Varity_R		0.042
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

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: rs35037408; hg19: chr12-1137217; COSMIC: COSV107425928; COSMIC: COSV107425928;