Genetic Variant ENST00000554572.5:c.-91+2333_-91+2334insGGG (chr14-64295199-A-ACCC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000554572.5(ESR2):c.-91+2333_-91+2334insGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 146,192 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 30)

Consequence

ESR2
ENST00000554572.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.117

Publications

1 publications found

Variant links:

Genes affected

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
familial medullary thyroid carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ovarian dysgenesis 8
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ESR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
ESR2	NM_001291712.2 link	c.-91+2331_-91+2333dupGGG	intron_variant	Intron 6 of 13	NP_001278641.1	Q92731-2F1D8N3
ESR2	NM_001291723.1 link	c.-90-12127_-90-12125dupGGG	intron_variant	Intron 1 of 8	NP_001278652.1	Q92731-2F1D8N3
ESR2	NR_073496.2 link	n.717-12127_717-12125dupGGG	intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000554572.5 link	c.-91+2333_-91+2334insGGG		intron_variant	Intron 6 of 13	1		ENSP00000450699.1		Q92731-2
ESR2	ENST00000358599.9 link	c.-90-12125_-90-12124insGGG		intron_variant	Intron 1 of 8	2		ENSP00000351412.5		Q92731-2

Frequencies

GnomAD3 genomes

AF:

0.0000205

AC:

AN:

146192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000521

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000215

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

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

GnomAD4 genome

AF:

0.0000205

AC:

AN:

146192

Hom.:

Cov.:

AF XY:

0.0000420

AC XY:

AN XY:

71460

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000521

AC:

AN:

38418

American (AMR)

AF:

0.00

AC:

AN:

14848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3328

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.000215

AC:

AN:

4662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66282

Other (OTH)

AF:

0.00

AC:

AN:

1974

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.12

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over