rs10995315

Variant names:

• chr10-62814811-G-A
• rs10995315
• NM_000399.5:c.170-343C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000399.5(EGR2):​c.170-343C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0576 in 152,252 control chromosomes in the GnomAD database, including 360 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.058 (360 hom., cov: 32)
• Consequence: EGR2 NM_000399.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 4 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

ENSG00000289487 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

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.170-343C>T		intron	N/A	NP_000390.2
	EGR2	NM_001410931.1		c.209-343C>T		intron	N/A	NP_001397860.1	A0A8I5KYI5
	EGR2	NM_001136177.3		c.170-343C>T		intron	N/A	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.170-343C>T		intron	N/A	ENSP00000242480.3	P11161-1
	EGR2	ENST00000439032.6	TSL:1	n.*185-343C>T		intron	N/A	ENSP00000509775.1	A0A8I5KVU0
	EGR2	ENST00000691610.1		c.209-343C>T		intron	N/A	ENSP00000509830.1	A0A8I5KYI5

Frequencies

GnomAD3 genomes AF: 0.0576 AC: 8767 AN: 152134 Hom.: 358 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.0845

Gnomad FIN AF: 0.0625

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0700

Gnomad OTH AF: 0.0554

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0576 AC: 8777 AN: 152252 Hom.: 360 Cov.: 32 AF XY: 0.0578 AC XY: 4299 AN XY: 74438

African (AFR) AF: 0.0152 AC: 632 AN: 41538

American (AMR) AF: 0.0560 AC: 857 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1037 AN: 5176

South Asian (SAS) AF: 0.0848 AC: 409 AN: 4822

European-Finnish (FIN) AF: 0.0625 AC: 663 AN: 10608

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0699 AC: 4755 AN: 68008

Other (OTH) AF: 0.0610 AC: 129 AN: 2116

Alfa AF: 0.0452 Hom.: 94

Bravo AF: 0.0547

Asia WGS AF: 0.140 AC: 487 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.66
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs10995315;

hg19: chr10-64574571;