10-62813552-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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 -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 VariationId is 256013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000399.5. 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
	EGR2	NM_000399.5	MANE Select	c.1086A>C	p.Arg362Arg	synonymous	Exon 2 of 2	NP_000390.2
	EGR2	NM_001410931.1		c.1125A>C	p.Arg375Arg	synonymous	Exon 3 of 3	NP_001397860.1	A0A8I5KYI5
	EGR2	NM_001136177.3		c.1086A>C	p.Arg362Arg	synonymous	Exon 3 of 3	NP_001129649.1	P11161-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR2	ENST00000242480.4	TSL:1 MANE Select	c.1086A>C	p.Arg362Arg	synonymous	Exon 2 of 2	ENSP00000242480.3	P11161-1
	EGR2	ENST00000439032.6	TSL:1	n.*1101A>C		non_coding_transcript_exon	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0
	EGR2	ENST00000439032.6	TSL:1	n.*1101A>C		3_prime_UTR	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0

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

GnomAD2 exomes AF: 0.0404 AC: 10134 AN: 250750 AF XY: 0.0399

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 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

African (AFR) AF: 0.0937 AC: 3135 AN: 33470

American (AMR) AF: 0.0613 AC: 2736 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26122

East Asian (EAS) AF: 0.136 AC: 5383 AN: 39682

South Asian (SAS) AF: 0.0676 AC: 5818 AN: 86092

European-Finnish (FIN) AF: 0.0293 AC: 1542 AN: 52556

Middle Eastern (MID) AF: 0.0414 AC: 239 AN: 5766

European-Non Finnish (NFE) AF: 0.0157 AC: 17462 AN: 1111802

Other (OTH) AF: 0.0350 AC: 2113 AN: 60368

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

African (AFR) AF: 0.0935 AC: 3697 AN: 39532

American (AMR) AF: 0.0439 AC: 652 AN: 14858

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 6 AN: 3340

East Asian (EAS) AF: 0.110 AC: 529 AN: 4806

South Asian (SAS) AF: 0.0854 AC: 391 AN: 4578

European-Finnish (FIN) AF: 0.0287 AC: 296 AN: 10328

Middle Eastern (MID) AF: 0.0341 AC: 9 AN: 264

European-Non Finnish (NFE) AF: 0.0160 AC: 1041 AN: 64932

Other (OTH) AF: 0.0461 AC: 93 AN: 2018

Alfa AF: 0.0281 Hom.: 72

Bravo AF: 0.0476

Asia WGS AF: 0.0950 AC: 330 AN: 3478

EpiCase AF: 0.0162

EpiControl AF: 0.0172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Charcot-Marie-Tooth disease type 1D (2)
-	1	1	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.0
DANN	Benign	0.54
PhyloP100		0.045
Mutation Taster		=99/1	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: rs45602133; hg19: chr10-64573312; COSMIC: COSV54346126; COSMIC: COSV54346126;