chr10-62813726-G-GGCTGCT

Variant names:

• chr10-62813726-G-GGCTGCT
• rs746688326
• NM_000399.5:c.906_911dupAGCAGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BS1_Supporting

The NM_000399.5(EGR2):​c.906_911dupAGCAGC​(p.Ala303_Ala304dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,610,048 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A304A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: EGR2 NM_000399.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.15
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000399.5
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000617 (9/1457944) while in subpopulation MID AF = 0.000523 (3/5740). AF 95% confidence interval is 0.000142. There are 1 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR2	NM_000399.5	MANE Select	c.906_911dupAGCAGC	p.Ala303_Ala304dup	disruptive_inframe_insertion	Exon 2 of 2	NP_000390.2
	EGR2	NM_001410931.1		c.945_950dupAGCAGC	p.Ala316_Ala317dup	disruptive_inframe_insertion	Exon 3 of 3	NP_001397860.1
	EGR2	NM_001136177.3		c.906_911dupAGCAGC	p.Ala303_Ala304dup	disruptive_inframe_insertion	Exon 3 of 3	NP_001129649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR2	ENST00000242480.4	TSL:1 MANE Select	c.906_911dupAGCAGC	p.Ala303_Ala304dup	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000242480.3
	EGR2	ENST00000439032.6	TSL:1	n.*921_*926dupAGCAGC		non_coding_transcript_exon	Exon 2 of 2	ENSP00000509775.1
	EGR2	ENST00000439032.6	TSL:1	n.*921_*926dupAGCAGC		3_prime_UTR	Exon 2 of 2	ENSP00000509775.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000850 AC: 2 AN: 235206 AF XY: 0.00000774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000947

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1457944 Hom.: 1 Cov.: 31 AF XY: 0.00000827 AC XY: 6 AN XY: 725208

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51000

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5740

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111064

Other (OTH) AF: 0.00 AC: 0 AN: 60166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Mar 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in apparent homozygous state in a patient with severe infantile muscular atrophy in the literature (PMID: 33600046); In-frame duplication of 2 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33600046)

Charcot-Marie-Tooth disease type 4E Uncertain:1

Sep 30, 2020

Institute of Human Genetics, Cologne University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.906_911dup, results in the insertion of 2 amino acid(s) of the EGR2 protein (p.Ala308_Ala309dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has been observed in individual(s) with autosomal recessive severe infantile muscular atrophy (PMID: 33600046). ClinVar contains an entry for this variant (Variation ID: 955998). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=81/19	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746688326; hg19: chr10-64573486;