Genetic Variant ESR2:p.Val328Val (chr14-64257333-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001437.3(ESR2):c.984G>A(p.Val328Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 1,613,366 control chromosomes in the GnomAD database, including 4,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 675 hom., cov: 31)

Exomes 𝑓: 0.044 ( 3351 hom. )

Consequence

ESR2
NM_001437.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0340

Publications

199 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 14-64257333-C-T is Benign according to our data. Variant chr14-64257333-C-T is described in ClinVar as Benign. ClinVar VariationId is 1228925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.034 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESR2	NM_001437.3	MANE Select	c.984G>A	p.Val328Val	synonymous	Exon 6 of 9	NP_001428.1
ESR2	NM_001040275.1		c.984G>A	p.Val328Val	synonymous	Exon 6 of 9	NP_001035365.1
ESR2	NM_001291712.2		c.984G>A	p.Val328Val	synonymous	Exon 11 of 14	NP_001278641.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESR2	ENST00000341099.6	TSL:1 MANE Select	c.984G>A	p.Val328Val	synonymous	Exon 6 of 9	ENSP00000343925.4
ESR2	ENST00000353772.7	TSL:1	c.984G>A	p.Val328Val	synonymous	Exon 6 of 9	ENSP00000335551.4
ESR2	ENST00000554572.5	TSL:1	c.984G>A	p.Val328Val	synonymous	Exon 11 of 14	ENSP00000450699.1

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10050

AN:

152108

Hom.:

674

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0893

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0441

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.0435

Gnomad FIN

AF:

0.0880

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0364

Gnomad OTH

AF:

0.0517

GnomAD2 exomes

AF:

0.0667

AC:

16779

AN:

251436

AF XY:

0.0624

show subpopulations

Gnomad AFR exome

AF:

0.0913

Gnomad AMR exome

AF:

0.0377

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.368

Gnomad FIN exome

AF:

0.0798

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0490

GnomAD4 exome

AF:

0.0445

AC:

64963

AN:

1461140

Hom.:

3351

Cov.:

AF XY:

0.0438

AC XY:

31842

AN XY:

726868

show subpopulations

African (AFR)

AF:

0.0923

AC:

3090

AN:

33460

American (AMR)

AF:

0.0388

AC:

1734

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

305

AN:

26136

East Asian (EAS)

AF:

0.320

AC:

12718

AN:

39698

South Asian (SAS)

AF:

0.0332

AC:

2859

AN:

86222

European-Finnish (FIN)

AF:

0.0781

AC:

4174

AN:

53418

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

5186

European-Non Finnish (NFE)

AF:

0.0329

AC:

36571

AN:

1111980

Other (OTH)

AF:

0.0567

AC:

3423

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3066

6132

9197

12263

15329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1514

3028

4542

6056

7570

<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:

0.0662

AC:

10080

AN:

152226

Hom.:

675

Cov.:

AF XY:

0.0687

AC XY:

5112

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0898

AC:

3729

AN:

41518

American (AMR)

AF:

0.0440

AC:

674

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3470

East Asian (EAS)

AF:

0.367

AC:

1894

AN:

5156

South Asian (SAS)

AF:

0.0435

AC:

210

AN:

4828

European-Finnish (FIN)

AF:

0.0880

AC:

934

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0364

AC:

2478

AN:

68028

Other (OTH)

AF:

0.0540

AC:

114

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

445

891

1336

1782

2227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0483

Hom.:

1065

Bravo

AF:

0.0651

Asia WGS

AF:

0.180

AC:

623

AN:

3478

EpiCase

AF:

0.0281

EpiControl

AF:

0.0314

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

ESR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.7

(source)

DANN

Benign

0.63

PhyloP100

-0.034

Mutation Taster

=99/1

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