rs1269056

Variant names:

• chr14-64277172-T-C
• rs1269056
• NM_001437.3:c.535+2809A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001437.3(ESR2):​c.535+2809A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 152,058 control chromosomes in the GnomAD database, including 34,141 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 (34141 hom., cov: 31)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77
• Publications: 15 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• 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	c.535+2809A>G		intron_variant	Intron 3 of 8	ENST00000341099.6	NP_001428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000341099.6	c.535+2809A>G		intron_variant	Intron 3 of 8	1	NM_001437.3	ENSP00000343925.4

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99384 AN: 151940 Hom.: 34096 Cov.: 31

Gnomad AFR AF: 0.878

Gnomad AMI AF: 0.781

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.564

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: 0.654 AC: 99483 AN: 152058 Hom.: 34141 Cov.: 31 AF XY: 0.649 AC XY: 48240 AN XY: 74314

African (AFR) AF: 0.878 AC: 36443 AN: 41504

American (AMR) AF: 0.558 AC: 8524 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2156 AN: 3466

East Asian (EAS) AF: 0.686 AC: 3540 AN: 5162

South Asian (SAS) AF: 0.482 AC: 2324 AN: 4826

European-Finnish (FIN) AF: 0.571 AC: 6030 AN: 10556

Middle Eastern (MID) AF: 0.538 AC: 157 AN: 292

European-Non Finnish (NFE) AF: 0.563 AC: 38261 AN: 67958

Other (OTH) AF: 0.633 AC: 1336 AN: 2112

Alfa AF: 0.623 Hom.: 25066

Bravo AF: 0.667

Asia WGS AF: 0.601 AC: 2091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.053
DANN	Benign	0.53
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1269056; hg19: chr14-64743890;