rs146116229

Variant names:

• chr10-62813239-C-G
• rs146116229
• NM_000399.5:c.1399G>C
• EGR2 p.Ala467Pro

Your query was ambiguous. Multiple possible variants found:

• chr10-62813239-C-G
• chr10-62813239-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.645
• Publications: 1 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, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -16 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 531709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1399G>C	p.Ala467Pro	missense	Exon 2 of 2	NP_000390.2
	EGR2	NM_001410931.1		c.1438G>C	p.Ala480Pro	missense	Exon 3 of 3	NP_001397860.1	A0A8I5KYI5
	EGR2	NM_001136177.3		c.1399G>C	p.Ala467Pro	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.1399G>C	p.Ala467Pro	missense	Exon 2 of 2	ENSP00000242480.3	P11161-1
	EGR2	ENST00000439032.6	TSL:1	n.*1414G>C		non_coding_transcript_exon	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0
	EGR2	ENST00000439032.6	TSL:1	n.*1414G>C		3_prime_UTR	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0

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

GnomAD2 exomes AF: 0.000356 AC: 74 AN: 208048 AF XY: 0.000253

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 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

African (AFR) AF: 0.00404 AC: 130 AN: 32202

American (AMR) AF: 0.000128 AC: 5 AN: 39052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.0000385 AC: 3 AN: 77940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48824

Middle Eastern (MID) AF: 0.000723 AC: 4 AN: 5532

European-Non Finnish (NFE) AF: 0.00000642 AC: 7 AN: 1090764

Other (OTH) AF: 0.000463 AC: 27 AN: 58358

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

African (AFR) AF: 0.00476 AC: 198 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.0000856 Hom.: 0

Bravo AF: 0.00155

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Charcot-Marie-Tooth disease, type I (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.65
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.088	T
Varity_R		0.24
gMVP		0.55
Mutation Taster		=82/18	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs146116229;

hg19: chr10-64572999;