14-64299934-T-C

Variant names:

• chr14-64299934-T-C
• rs2978381
• ENST00000554572.5:c.-371+1434A>G

Variant summary

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

The NM_001291712.2(ESR2):​c.-371+1434A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 151,962 control chromosomes in the GnomAD database, including 22,764 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 0.52 (22764 hom., cov: 31)
• Consequence: ESR2 NM_001291712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.906
• Publications: 20 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291712.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	NM_001291712.2		c.-371+1434A>G		intron	N/A	NP_001278641.1	Q92731-2
	ESR2	NM_001291723.1		c.-90-16859A>G		intron	N/A	NP_001278652.1	Q92731-2
	ESR2	NR_073496.2		n.717-16859A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000554572.5	TSL:1	c.-371+1434A>G		intron	N/A	ENSP00000450699.1	Q92731-2
	ESR2	ENST00000358599.9	TSL:2	c.-90-16859A>G		intron	N/A	ENSP00000351412.5	Q92731-2

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78721 AN: 151844 Hom.: 22729 Cov.: 31

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.514

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

GnomAD4 genome AF: 0.519 AC: 78808 AN: 151962 Hom.: 22764 Cov.: 31 AF XY: 0.508 AC XY: 37749 AN XY: 74272

African (AFR) AF: 0.790 AC: 32759 AN: 41452

American (AMR) AF: 0.453 AC: 6908 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1801 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1609 AN: 5164

South Asian (SAS) AF: 0.403 AC: 1940 AN: 4818

European-Finnish (FIN) AF: 0.336 AC: 3545 AN: 10544

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28506 AN: 67942

Other (OTH) AF: 0.509 AC: 1075 AN: 2112

Alfa AF: 0.461 Hom.: 51652

Bravo AF: 0.541

Asia WGS AF: 0.413 AC: 1440 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.96
DANN	Benign	0.51
PhyloP100		-0.91
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: rs2978381; hg19: chr14-64766652;