10-62813552-T-G

Variant names:

• chr10-62813552-T-G
• rs45602133
• NM_000399.5:c.1086A>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000399.5(EGR2):​c.1086A>C​(p.Arg362Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,606,002 control chromosomes in the GnomAD database, including 1,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (245 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1171 hom.)
• Consequence: EGR2 NM_000399.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:2 B:7
• Conservation: PhyloP100: 0.0450

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-62813552-T-G is Benign according to our data. Variant chr10-62813552-T-G is described in ClinVar as [Benign]. Clinvar id is 256013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-62813552-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.045 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGR2	NM_000399.5	c.1086A>C	p.Arg362Arg	synonymous_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.1086A>C	p.Arg362Arg	synonymous_variant	Exon 2 of 2	1	NM_000399.5	ENSP00000242480.3

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 6730 AN: 145366 Hom.: 244 Cov.: 32

Gnomad AFR AF: 0.0936

Gnomad AMI AF: 0.0265

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.00180

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0853

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.0355

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0461

GnomAD3 exomes AF: 0.0404 AC: 10134 AN: 250750 Hom.: 351 AF XY: 0.0399 AC XY: 5414 AN XY: 135632

Gnomad AFR exome AF: 0.0881

Gnomad AMR exome AF: 0.0654

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0927

Gnomad SAS exome AF: 0.0689

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0263 AC: 38481 AN: 1460516 Hom.: 1171 Cov.: 31 AF XY: 0.0271 AC XY: 19700 AN XY: 726544

Gnomad4 AFR exome AF: 0.0937

Gnomad4 AMR exome AF: 0.0613

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.136

Gnomad4 SAS exome AF: 0.0676

Gnomad4 FIN exome AF: 0.0293

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0350

GnomAD4 genome AF: 0.0463 AC: 6736 AN: 145486 Hom.: 245 Cov.: 32 AF XY: 0.0470 AC XY: 3348 AN XY: 71292

Gnomad4 AFR AF: 0.0935

Gnomad4 AMR AF: 0.0439

Gnomad4 ASJ AF: 0.00180

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.0854

Gnomad4 FIN AF: 0.0287

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0461

Alfa AF: 0.0274 Hom.: 69

Bravo AF: 0.0476

Asia WGS AF: 0.0950 AC: 330 AN: 3478

EpiCase AF: 0.0162

EpiControl AF: 0.0172

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 29, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease type 1D Uncertain:1 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. -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease, type I Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.0
DANN	Benign	0.54

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: rs45602133; hg19: chr10-64573312; COSMIC: COSV54346126; COSMIC: COSV54346126;