14-64296935-A-G

Variant names:

• chr14-64296935-A-G
• rs2987983
• ENST00000554572.5:c.-91+598T>C

Variant summary

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

The ENST00000554572.5(ESR2):​c.-91+598T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 152,030 control chromosomes in the GnomAD database, including 13,007 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 0.39 (13007 hom., cov: 32)
• Consequence: ESR2 ENST00000554572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.248
• Publications: 60 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000554572.5. 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_001291712.2		c.-91+598T>C		intron	N/A	NP_001278641.1
	ESR2	NM_001291723.1		c.-90-13860T>C		intron	N/A	NP_001278652.1
	ESR2	NR_073496.2		n.717-13860T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000554572.5	TSL:1	c.-91+598T>C		intron	N/A	ENSP00000450699.1
	ESR2	ENST00000358599.9	TSL:2	c.-90-13860T>C		intron	N/A	ENSP00000351412.5

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59828 AN: 151912 Hom.: 12995 Cov.: 32

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.405

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

GnomAD4 genome AF: 0.394 AC: 59879 AN: 152030 Hom.: 13007 Cov.: 32 AF XY: 0.387 AC XY: 28714 AN XY: 74290

African (AFR) AF: 0.581 AC: 24092 AN: 41462

American (AMR) AF: 0.362 AC: 5540 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1450 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1569 AN: 5164

South Asian (SAS) AF: 0.351 AC: 1690 AN: 4812

European-Finnish (FIN) AF: 0.233 AC: 2459 AN: 10552

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21703 AN: 67978

Other (OTH) AF: 0.400 AC: 842 AN: 2106

Alfa AF: 0.351 Hom.: 15645

Bravo AF: 0.411

Asia WGS AF: 0.351 AC: 1222 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.65
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2987983; hg19: chr14-64763653;