NM_000399.5:c.169+261G>C

Variant names:

• chr10-62815600-C-G
• rs2297489
• NM_000399.5:c.169+261G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000399.5(EGR2):​c.169+261G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0578 in 152,320 control chromosomes in the GnomAD database, including 362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.058 (362 hom., cov: 34)
• Consequence: EGR2 NM_000399.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.764
• Publications: 3 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

ENSG00000289487 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-62815600-C-G is Benign according to our data. Variant chr10-62815600-C-G is described in ClinVar as Benign. ClinVar VariationId is 669763.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 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.169+261G>C		intron	N/A	NP_000390.2
	EGR2	NM_001410931.1		c.208+261G>C		intron	N/A	NP_001397860.1
	EGR2	NM_001136177.3		c.169+261G>C		intron	N/A	NP_001129649.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR2	ENST00000242480.4	TSL:1 MANE Select	c.169+261G>C		intron	N/A	ENSP00000242480.3
	EGR2	ENST00000439032.6	TSL:1	n.430G>C		non_coding_transcript_exon	Exon 1 of 2	ENSP00000509775.1
	EGR2	ENST00000691610.1		c.208+261G>C		intron	N/A	ENSP00000509830.1

Frequencies

GnomAD3 genomes AF: 0.0577 AC: 8787 AN: 152202 Hom.: 360 Cov.: 34

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.0850

Gnomad FIN AF: 0.0625

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0564

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0578 AC: 8797 AN: 152320 Hom.: 362 Cov.: 34 AF XY: 0.0578 AC XY: 4303 AN XY: 74470

African (AFR) AF: 0.0153 AC: 636 AN: 41588

American (AMR) AF: 0.0560 AC: 858 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3470

East Asian (EAS) AF: 0.200 AC: 1032 AN: 5160

South Asian (SAS) AF: 0.0853 AC: 412 AN: 4830

European-Finnish (FIN) AF: 0.0625 AC: 663 AN: 10616

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0701 AC: 4770 AN: 68026

Other (OTH) AF: 0.0619 AC: 131 AN: 2116

Alfa AF: 0.0593 Hom.: 34

Bravo AF: 0.0549

Asia WGS AF: 0.142 AC: 492 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		0.76
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: rs2297489; hg19: chr10-64575360;