rs1422314988

Positions:

• chr10-62813394-C-A
• chr10-62813394-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000399.5(EGR2):​c.1244G>T​(p.Arg415Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a zinc_finger_region C2H2-type 3 (size 22) in uniprot entity EGR2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000399.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGR2	NM_000399.5	c.1244G>T	p.Arg415Leu	missense_variant	2/2	ENST00000242480.4	NP_000390.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGR2	ENST00000242480.4	c.1244G>T	p.Arg415Leu	missense_variant	2/2	1	NM_000399.5	ENSP00000242480.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.76
MutPred		0.53		Gain of catalytic residue at R415 (P = 0.0432);.;Gain of catalytic residue at R415 (P = 0.0432);
MVP		0.85
MPC		1.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs1422314988; hg19: chr10-64573154;