rs281865136

Variant names:

• chr10-62813562-C-T
• rs281865136
• NM_000399.5:c.1076G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000399.5(EGR2):​c.1076G>A​(p.Arg359Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R359G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:2 O:1
• Conservation: PhyloP100: 7.91
• Publications: 2 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000399.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-62813563-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1422578.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 10-62813562-C-T is Pathogenic according to our data. Variant chr10-62813562-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 41007.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1076G>A	p.Arg359Gln	missense	Exon 2 of 2	NP_000390.2
	EGR2	NM_001410931.1		c.1115G>A	p.Arg372Gln	missense	Exon 3 of 3	NP_001397860.1	A0A8I5KYI5
	EGR2	NM_001136177.3		c.1076G>A	p.Arg359Gln	missense	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.1076G>A	p.Arg359Gln	missense	Exon 2 of 2	ENSP00000242480.3	P11161-1
	EGR2	ENST00000439032.6	TSL:1	n.*1091G>A		non_coding_transcript_exon	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0
	EGR2	ENST00000439032.6	TSL:1	n.*1091G>A		3_prime_UTR	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease (1)
-	1	-	Charcot-Marie-Tooth disease type 1D (2)
1	-	-	Charcot-Marie-Tooth disease, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.86		Loss of MoRF binding (P = 0.0252)
MVP		0.83
MPC		2.0
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.78
gMVP		0.89
Mutation Taster		=17/83	disease causing (ClinVar)

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: rs281865136; hg19: chr10-64573322; COSMIC: COSV108789121;