14-64272261-G-C

Variant names:

• chr14-64272261-G-C
• rs1256039
• NM_001437.3:c.536-3350C>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.536-3350C>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 152,122 control chromosomes in the GnomAD database, including 34,167 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 (34167 hom., cov: 32)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 6 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 = 0.87 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	NM_001437.3	MANE Select	c.536-3350C>G		intron	N/A	NP_001428.1
	ESR2	NM_001040275.1		c.536-3350C>G		intron	N/A	NP_001035365.1
	ESR2	NM_001291712.2		c.536-3350C>G		intron	N/A	NP_001278641.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000341099.6	TSL:1 MANE Select	c.536-3350C>G		intron	N/A	ENSP00000343925.4
	ESR2	ENST00000353772.7	TSL:1	c.536-3350C>G		intron	N/A	ENSP00000335551.4
	ESR2	ENST00000554572.5	TSL:1	c.536-3350C>G		intron	N/A	ENSP00000450699.1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99468 AN: 152004 Hom.: 34126 Cov.: 32

Gnomad AFR AF: 0.878

Gnomad AMI AF: 0.781

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.633

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

GnomAD4 genome AF: 0.654 AC: 99559 AN: 152122 Hom.: 34167 Cov.: 32 AF XY: 0.650 AC XY: 48291 AN XY: 74350

African (AFR) AF: 0.878 AC: 36462 AN: 41530

American (AMR) AF: 0.559 AC: 8546 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2161 AN: 3472

East Asian (EAS) AF: 0.687 AC: 3563 AN: 5186

South Asian (SAS) AF: 0.482 AC: 2322 AN: 4814

European-Finnish (FIN) AF: 0.572 AC: 6027 AN: 10534

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38278 AN: 67980

Other (OTH) AF: 0.628 AC: 1328 AN: 2114

Alfa AF: 0.607 Hom.: 3460

Bravo AF: 0.667

Asia WGS AF: 0.586 AC: 2039 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.48
DANN	Benign	0.30
PhyloP100		-1.3
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: rs1256039; hg19: chr14-64738979;