chr12-1027951-G-C

Position:

• chr12-1027951-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_178040.4(ERC1):​c.48G>C​(p.Gln16His) variant causes a missense change. The variant allele was found at a frequency of 0.000707 in 1,613,490 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (13 hom.)
• Consequence: ERC1 NM_178040.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.37

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]

ERC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071875453).
• BP6: Variant 12-1027951-G-C is Benign according to our data. Variant chr12-1027951-G-C is described in ClinVar as [Benign]. Clinvar id is 3033364.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000854 (130/152306) while in subpopulation EAS AF= 0.022 (114/5186). AF 95% confidence interval is 0.0187. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERC1	NM_178040.4	c.48G>C	p.Gln16His	missense_variant	2/19	ENST00000360905.9	NP_829884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERC1	ENST00000360905.9	c.48G>C	p.Gln16His	missense_variant	2/19	1	NM_178040.4	ENSP00000354158.3

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00154 AC: 387 AN: 251232 Hom.: 3 AF XY: 0.00158 AC XY: 214 AN XY: 135760

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0190

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000692 AC: 1011 AN: 1461184 Hom.: 13 Cov.: 31 AF XY: 0.000717 AC XY: 521 AN XY: 726728

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0203

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74476

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0220

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000122 Hom.: 0

Bravo AF: 0.00114

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00146 AC: 177

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ERC1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;.;T;.;.;.;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0072	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.044	D
MutationAssessor	Benign	0.55	.;N;.;N;.;N;N;N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.88	.;N;N;N;.;.;N;.;N
REVEL	Uncertain	0.29
Sift	Benign	0.078	.;T;T;T;.;.;T;.;T
Sift4G	Uncertain	0.051	T;T;T;T;D;T;T;T;T
Polyphen		0.92, 0.99	.;P;.;D;.;.;P;D;.
Vest4		0.57, 0.61, 0.61, 0.57, 0.57, 0.61, 0.61
MutPred		0.15		Gain of catalytic residue at Q16 (P = 0.0236);Gain of catalytic residue at Q16 (P = 0.0236);Gain of catalytic residue at Q16 (P = 0.0236);Gain of catalytic residue at Q16 (P = 0.0236);Gain of catalytic residue at Q16 (P = 0.0236);Gain of catalytic residue at Q16 (P = 0.0236);Gain of catalytic residue at Q16 (P = 0.0236);Gain of catalytic residue at Q16 (P = 0.0236);Gain of catalytic residue at Q16 (P = 0.0236);
MVP		0.82
MPC		1.0
ClinPred		0.054	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.48

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: rs61740169; hg19: chr12-1137117;