rs146116229

chr10-62813239-C-Gchr10-62813239-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_000399.5(EGR2):c.1399G>C(p.Ala467Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,567,208 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A467T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.645

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035232902).
• BP6: Variant 10-62813239-C-G is Benign according to our data. Variant chr10-62813239-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 531709.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00137 (208/152324) while in subpopulation AFR AF= 0.00476 (198/41590). AF 95% confidence interval is 0.00422. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGR2	NM_000399.5	c.1399G>C	p.Ala467Pro	missense_variant	2/2	ENST00000242480.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGR2	ENST00000242480.4	c.1399G>C	p.Ala467Pro	missense_variant	2/2	1	NM_000399.5	A1

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000356 AC: 74 AN: 208048 Hom.: 0 AF XY: 0.000253 AC XY: 28 AN XY: 110492

Gnomad AFR exome AF: 0.00423

Gnomad AMR exome AF: 0.000103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000313

Gnomad OTH exome AF: 0.000202

GnomAD4 exome AF: 0.000124 AC: 176 AN: 1414884 Hom.: 1 Cov.: 31 AF XY: 0.000109 AC XY: 76 AN XY: 699668

Gnomad4 AFR exome AF: 0.00404

Gnomad4 AMR exome AF: 0.000128

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000385

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000642

Gnomad4 OTH exome AF: 0.000463

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74490

Gnomad4 AFR AF: 0.00476

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000856 Hom.: 0

Bravo AF: 0.00155

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000454 AC: 55

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2020	This variant is associated with the following publications: (PMID: 32376792) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 09, 2019	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	0.60	D;D;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.088	T;T;T
Polyphen		0.61	P;B;P
Vest4		0.27
MVP		0.35
MPC		1.1
ClinPred		0.028	T
GERP RS		4.2
Varity_R		0.24
gMVP		0.55

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: rs146116229; hg19: chr10-64572999;