ENST00000439032.6:n.*1733T>A

Variant names:

• chr10-62812920-A-T
• rs61865883
• ENST00000439032.6:n.*1733T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000439032.6(EGR2):​n.*1733T>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 337,154 control chromosomes in the GnomAD database, including 836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (314 hom., cov: 32)
  • Exomes 𝑓: 0.069 (522 hom.)
• Consequence: EGR2 ENST00000439032.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.86
• Publications: 6 publications found

Genes affected

EGR2 (HGNC:3239): (early growth response 2) The protein encoded by this gene is a transcription factor with three tandem C2H2-type zinc fingers. Defects in this gene are associated with Charcot-Marie-Tooth disease type 1D (CMT1D), Charcot-Marie-Tooth disease type 4E (CMT4E), and with Dejerine-Sottas syndrome (DSS). Multiple transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

EGR2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Charcot-Marie-Tooth disease

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 1D

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 3

  Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-62812920-A-T is Benign according to our data. Variant chr10-62812920-A-T is described in ClinVar as [Benign]. Clinvar id is 300273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGR2	NM_000399.5	c.*287T>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000242480.4	NP_000390.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGR2	ENST00000242480.4	c.*287T>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_000399.5	ENSP00000242480.3

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8506 AN: 152186 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0595

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0663

Gnomad FIN AF: 0.0625

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0701

Gnomad OTH AF: 0.0526

GnomAD4 exome AF: 0.0691 AC: 12767 AN: 184850 Hom.: 522 Cov.: 2 AF XY: 0.0685 AC XY: 6407 AN XY: 93554

African (AFR) AF: 0.0165 AC: 97 AN: 5880

American (AMR) AF: 0.0548 AC: 420 AN: 7662

Ashkenazi Jewish (ASJ) AF: 0.0414 AC: 288 AN: 6956

East Asian (EAS) AF: 0.127 AC: 2088 AN: 16388

South Asian (SAS) AF: 0.0604 AC: 221 AN: 3656

European-Finnish (FIN) AF: 0.0640 AC: 874 AN: 13658

Middle Eastern (MID) AF: 0.0522 AC: 52 AN: 996

European-Non Finnish (NFE) AF: 0.0673 AC: 7897 AN: 117364

Other (OTH) AF: 0.0675 AC: 830 AN: 12290

GnomAD4 genome AF: 0.0559 AC: 8516 AN: 152304 Hom.: 314 Cov.: 32 AF XY: 0.0559 AC XY: 4165 AN XY: 74472

African (AFR) AF: 0.0144 AC: 600 AN: 41576

American (AMR) AF: 0.0594 AC: 908 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3472

East Asian (EAS) AF: 0.165 AC: 853 AN: 5182

South Asian (SAS) AF: 0.0667 AC: 322 AN: 4826

European-Finnish (FIN) AF: 0.0625 AC: 663 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0700 AC: 4765 AN: 68024

Other (OTH) AF: 0.0582 AC: 123 AN: 2112

Alfa AF: 0.0589 Hom.: 33

Bravo AF: 0.0538

Asia WGS AF: 0.127 AC: 440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 1D Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		1.9
Mutation Taster		=100/0	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: rs61865883; hg19: chr10-64572680;