chr14-64309058-C-T

Variant names:

• chr14-64309058-C-T
• rs10137185
• ENST00000554572.5:c.-767-5399G>A

Variant summary

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

The ENST00000554572.5(ESR2):​c.-767-5399G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,040 control chromosomes in the GnomAD database, including 2,723 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 0.16 (2723 hom., cov: 32)
• Consequence: ESR2 ENST00000554572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• Publications: 19 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=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR2	NM_001291712.2	c.-767-5399G>A		intron_variant	Intron 2 of 13		NP_001278641.1
ESR2	NM_001291723.1	c.-90-25983G>A		intron_variant	Intron 1 of 8		NP_001278652.1
ESR2	NR_073496.2	n.717-25983G>A		intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000554572.5	c.-767-5399G>A		intron_variant	Intron 2 of 13	1		ENSP00000450699.1
ESR2	ENST00000358599.9	c.-90-25983G>A		intron_variant	Intron 1 of 8	2		ENSP00000351412.5

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24557 AN: 151922 Hom.: 2708 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.0581

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.162 AC: 24617 AN: 152040 Hom.: 2723 Cov.: 32 AF XY: 0.158 AC XY: 11763 AN XY: 74326

African (AFR) AF: 0.304 AC: 12615 AN: 41446

American (AMR) AF: 0.159 AC: 2426 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3470

East Asian (EAS) AF: 0.0965 AC: 500 AN: 5180

South Asian (SAS) AF: 0.0577 AC: 278 AN: 4814

European-Finnish (FIN) AF: 0.107 AC: 1130 AN: 10572

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.101 AC: 6860 AN: 67990

Other (OTH) AF: 0.150 AC: 317 AN: 2108

Alfa AF: 0.120 Hom.: 5822

Bravo AF: 0.179

Asia WGS AF: 0.110 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.49
PhyloP100		-0.054
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: rs10137185; hg19: chr14-64775776;