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rs1256049

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001437.3(ESR2):c.984G>A(p.Val328=) 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

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0340
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ESR2NM_001437.3 linkuse as main transcriptc.984G>A p.Val328= synonymous_variant 6/9 ENST00000341099.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ESR2ENST00000341099.6 linkuse as main transcriptc.984G>A p.Val328= synonymous_variant 6/91 NM_001437.3 P1Q92731-1

Frequencies

GnomAD3 genomes
AF:
0.0661
AC:
10050
AN:
152108
Hom.:
674
Cov.:
31
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
GnomAD3 exomes
AF:
0.0667
AC:
16779
AN:
251436
Hom.:
1557
AF XY:
0.0624
AC XY:
8474
AN XY:
135902
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 SAS exome
AF:
0.0336
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.:
31
AF XY:
0.0438
AC XY:
31842
AN XY:
726868
show subpopulations
Gnomad4 AFR exome
AF:
0.0923
Gnomad4 AMR exome
AF:
0.0388
Gnomad4 ASJ exome
AF:
0.0117
Gnomad4 EAS exome
AF:
0.320
Gnomad4 SAS exome
AF:
0.0332
Gnomad4 FIN exome
AF:
0.0781
Gnomad4 NFE exome
AF:
0.0329
Gnomad4 OTH exome
AF:
0.0567
GnomAD4 genome
AF:
0.0662
AC:
10080
AN:
152226
Hom.:
675
Cov.:
31
AF XY:
0.0687
AC XY:
5112
AN XY:
74410
show subpopulations
Gnomad4 AFR
AF:
0.0898
Gnomad4 AMR
AF:
0.0440
Gnomad4 ASJ
AF:
0.0110
Gnomad4 EAS
AF:
0.367
Gnomad4 SAS
AF:
0.0435
Gnomad4 FIN
AF:
0.0880
Gnomad4 NFE
AF:
0.0364
Gnomad4 OTH
AF:
0.0540
Alfa
AF:
0.0409
Hom.:
259
Bravo
AF:
0.0651
Asia WGS
AF:
0.180
AC:
623
AN:
3478
EpiCase
AF:
0.0281
EpiControl
AF:
0.0314

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxJul 09, 2018This variant is associated with the following publications: (PMID: 11231990) -
ESR2-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 22, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.38
Cadd
Benign
7.7
Dann
Benign
0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1256049; hg19: chr14-64724051; COSMIC: COSV50829277; API