rs281865137

Variant names:

• chr10-62813496-C-A
• rs281865137
• NM_000399.5:c.1142G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-62813496-C-A
• chr10-62813496-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000399.5(EGR2):​c.1142G>T​(p.Arg381Leu) 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. R381C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.89
• 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 16 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, 8 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 chr10-62813497-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 637524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 10-62813496-C-A is Pathogenic according to our data. Variant chr10-62813496-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1075624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1142G>T	p.Arg381Leu	missense	Exon 2 of 2	NP_000390.2
	EGR2	NM_001410931.1		c.1181G>T	p.Arg394Leu	missense	Exon 3 of 3	NP_001397860.1	A0A8I5KYI5
	EGR2	NM_001136177.3		c.1142G>T	p.Arg381Leu	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.1142G>T	p.Arg381Leu	missense	Exon 2 of 2	ENSP00000242480.3	P11161-1
	EGR2	ENST00000439032.6	TSL:1	n.*1157G>T		non_coding_transcript_exon	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0
	EGR2	ENST00000439032.6	TSL:1	n.*1157G>T		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, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.79
MutPred		0.77		Loss of MoRF binding (P = 0.0133)
MVP		0.87
MPC		2.1
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.89
gMVP		0.95
Mutation Taster		=1/99	disease causing

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: rs281865137; hg19: chr10-64573256;