10-62813710-AGGCGGCGGC-AGGCGGCGGCGGCGGC

Variant names:

• chr10-62813710-A-AGGCGGC
• rs753747037
• NM_000399.5:c.922_927dupGCCGCC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4 BS1_Supporting

The NM_000399.5(EGR2):​c.922_927dupGCCGCC​(p.Ala308_Ala309dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,611,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: EGR2 NM_000399.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.267

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000399.5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000105 (16/152056) while in subpopulation NFE AF= 0.000206 (14/68000). AF 95% confidence interval is 0.000124. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGR2	NM_000399.5	c.922_927dupGCCGCC	p.Ala308_Ala309dup	conservative_inframe_insertion	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.922_927dupGCCGCC	p.Ala308_Ala309dup	conservative_inframe_insertion	Exon 2 of 2	1	NM_000399.5	ENSP00000242480.3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000616 AC: 15 AN: 243670 Hom.: 0 AF XY: 0.0000676 AC XY: 9 AN XY: 133136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 163 AN: 1459812 Hom.: 0 Cov.: 31 AF XY: 0.000103 AC XY: 75 AN XY: 726102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000575

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74254

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Aug 15, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously, as c.906_911dup, in the homozygous state as a variant of uncertain significance in an infant with severe infantile muscular atrophy (Keller et al., 2021); In-frame insertion of 2 amino acids in a repetitive region with no known function; This variant is associated with the following publications: (PMID: 33600046) -

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

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.922_927dup, 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 (rs753747037, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of autosomal recessive congenital hypomyelinating neuropathy (PMID: 33600046). ClinVar contains an entry for this variant (Variation ID: 842568). 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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs753747037; hg19: chr10-64573470;