Genetic Variant ESR2:c.536-1842T>C (chr14-64270753-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001437.3(ESR2):c.536-1842T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 152,094 control chromosomes in the GnomAD database, including 34,182 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 0.65 ( 34182 hom., cov: 32)

Consequence

ESR2
NM_001437.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.71

Publications

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.05).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR2	NM_001437.3 link	c.536-1842T>C		intron_variant	Intron 3 of 8	ENST00000341099.6	NP_001428.1	Q92731-1Q7LCB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000341099.6 link	c.536-1842T>C		intron_variant	Intron 3 of 8	1	NM_001437.3	ENSP00000343925.4		Q92731-1

Frequencies

GnomAD3 genomes

AF:

0.655

AC:

99472

AN:

151976

Hom.:

34141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.878

Gnomad AMI

AF:

0.781

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.623

Gnomad EAS

AF:

0.687

Gnomad SAS

AF:

0.484

Gnomad FIN

AF:

0.572

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.563

Gnomad OTH

AF:

0.634

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

GnomAD4 genome

AF:

0.655

AC:

99563

AN:

152094

Hom.:

34182

Cov.:

AF XY:

0.650

AC XY:

48287

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.878

AC:

36479

AN:

41540

American (AMR)

AF:

0.559

AC:

8534

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.623

AC:

2161

AN:

3470

East Asian (EAS)

AF:

0.687

AC:

3545

AN:

5162

South Asian (SAS)

AF:

0.483

AC:

2329

AN:

4818

European-Finnish (FIN)

AF:

0.572

AC:

6031

AN:

10552

Middle Eastern (MID)

AF:

0.541

AC:

159

AN:

294

European-Non Finnish (NFE)

AF:

0.563

AC:

38284

AN:

67956

Other (OTH)

AF:

0.629

AC:

1329

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1628

3256

4885

6513

8141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

780

1560

2340

3120

3900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.206

Hom.:

1464

Bravo

AF:

0.667

Asia WGS

AF:

0.587

AC:

2042

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.16

(source)

DANN

Benign

0.16

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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