12-1028203-C-T

Variant names:

• chr12-1028203-C-T
• rs138791726
• NM_178040.4:c.300C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_178040.4(ERC1):​c.300C>T​(p.Tyr100Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,614,166 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: ERC1 NM_178040.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.69

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 12-1028203-C-T is Benign according to our data. Variant chr12-1028203-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3038730.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS2: High AC in GnomAd4 at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERC1	NM_178040.4	c.300C>T	p.Tyr100Tyr	synonymous_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.300C>T	p.Tyr100Tyr	synonymous_variant	Exon 2 of 19	1	NM_178040.4	ENSP00000354158.3

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000966 AC: 243 AN: 251462 Hom.: 1 AF XY: 0.000898 AC XY: 122 AN XY: 135902

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00224 AC: 3276 AN: 1461892 Hom.: 6 Cov.: 32 AF XY: 0.00219 AC XY: 1591 AN XY: 727248

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00278

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74464

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ERC1-related disorder Benign:1

Feb 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.11
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs138791726; hg19: chr12-1137369;