14-64214130-A-G

Variant names:

• chr14-64214130-A-G
• rs1152591
• NM_182914.3:c.19057-64A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):​c.19057-64A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,612,370 control chromosomes in the GnomAD database, including 238,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31859 hom., cov: 32)
  • Exomes 𝑓: 0.53 (206321 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.27
• Publications: 81 publications found

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-64214130-A-G is Benign according to our data. Variant chr14-64214130-A-G is described in ClinVar as Benign. ClinVar VariationId is 1258595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.19057-64A>G		intron_variant	Intron 105 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.19057-64A>G		intron_variant	Intron 105 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95413 AN: 151942 Hom.: 31806 Cov.: 32

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.610

GnomAD4 exome AF: 0.527 AC: 769658 AN: 1460310 Hom.: 206321 Cov.: 36 AF XY: 0.526 AC XY: 381820 AN XY: 726468

African (AFR) AF: 0.885 AC: 29520 AN: 33342

American (AMR) AF: 0.516 AC: 22959 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 16124 AN: 26120

East Asian (EAS) AF: 0.683 AC: 27084 AN: 39682

South Asian (SAS) AF: 0.505 AC: 43501 AN: 86134

European-Finnish (FIN) AF: 0.523 AC: 27815 AN: 53234

Middle Eastern (MID) AF: 0.565 AC: 3255 AN: 5758

European-Non Finnish (NFE) AF: 0.509 AC: 565816 AN: 1111212

Other (OTH) AF: 0.557 AC: 33584 AN: 60334

GnomAD4 genome AF: 0.628 AC: 95522 AN: 152060 Hom.: 31859 Cov.: 32 AF XY: 0.624 AC XY: 46409 AN XY: 74328

African (AFR) AF: 0.871 AC: 36135 AN: 41492

American (AMR) AF: 0.544 AC: 8307 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2134 AN: 3472

East Asian (EAS) AF: 0.721 AC: 3727 AN: 5168

South Asian (SAS) AF: 0.515 AC: 2484 AN: 4826

European-Finnish (FIN) AF: 0.532 AC: 5619 AN: 10560

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.515 AC: 35008 AN: 67962

Other (OTH) AF: 0.609 AC: 1283 AN: 2106

Alfa AF: 0.560 Hom.: 70395

Bravo AF: 0.643

Asia WGS AF: 0.624 AC: 2169 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.049
DANN	Benign	0.29
PhyloP100		-2.3
PromoterAI		0.017	Neutral
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: rs1152591; hg19: chr14-64680848; COSMIC: COSV59952164; COSMIC: COSV59952164;