Genetic Variant ESR2:c.*633C>T (chr14-64234324-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000557772.5(ESR2):c.*633C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,464 control chromosomes in the GnomAD database, including 3,920 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 0.21 ( 3904 hom., cov: 31)

Exomes 𝑓: 0.20 ( 16 hom. )

Consequence

ESR2
ENST00000557772.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

Publications

10 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:

LOC124903328 (HGNC:):

LOC124903328 links:

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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=-0.8).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557772.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ESR2	NM_001437.3	MANE Select	c.1406+646C>T	intron	N/A	NP_001428.1
ESR2	NM_001040275.1		c.1406+646C>T	intron	N/A	NP_001035365.1
ESR2	NM_001291712.2		c.1406+646C>T	intron	N/A	NP_001278641.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ESR2	ENST00000557772.5	TSL:1	c.*633C>T	3_prime_UTR	Exon 7 of 7	ENSP00000451582.1
ESR2	ENST00000341099.6	TSL:1 MANE Select	c.1406+646C>T	intron	N/A	ENSP00000343925.4
ESR2	ENST00000353772.7	TSL:1	c.1406+646C>T	intron	N/A	ENSP00000335551.4

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31741

AN:

151750

Hom.:

3911

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0900

Gnomad AMI

AF:

0.431

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.122

Gnomad SAS

AF:

0.247

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.220

GnomAD4 exome

AF:

0.205

AC:

122

AN:

596

Hom.:

Cov.:

AF XY:

0.201

AC XY:

AN XY:

364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.167

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.231

AC:

AN:

242

Middle Eastern (MID)

AF:

0.100

AC:

AN:

European-Non Finnish (NFE)

AF:

0.202

AC:

AN:

272

Other (OTH)

AF:

0.147

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.209

AC:

31722

AN:

151868

Hom.:

3904

Cov.:

AF XY:

0.205

AC XY:

15251

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.0897

AC:

3717

AN:

41422

American (AMR)

AF:

0.182

AC:

2773

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1112

AN:

3468

East Asian (EAS)

AF:

0.122

AC:

628

AN:

5152

South Asian (SAS)

AF:

0.248

AC:

1191

AN:

4804

European-Finnish (FIN)

AF:

0.235

AC:

2471

AN:

10520

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18891

AN:

67924

Other (OTH)

AF:

0.216

AC:

455

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1193

2386

3578

4771

5964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

346

692

1038

1384

1730

<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:

0.235

Hom.:

1707

Bravo

AF:

0.198

Asia WGS

AF:

0.192

AC:

668

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.1

(source)

DANN

Benign

0.79

PhyloP100

1.3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over