chr14-64225135-C-T

Variant names:

• chr14-64225135-C-T
• rs12434245
• NM_182914.3:c.20516+90C>T

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.20516+90C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,564,992 control chromosomes in the GnomAD database, including 4,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (327 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4607 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.435
• Publications: 9 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=-0.9).
• BP6: Variant 14-64225135-C-T is Benign according to our data. Variant chr14-64225135-C-T is described in ClinVar as [Benign]. Clinvar id is 1295983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.20516+90C>T		intron_variant	Intron 115 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.20516+90C>T		intron_variant	Intron 115 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8502 AN: 152004 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0596

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.00906

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.0929

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0796

Gnomad OTH AF: 0.0536

GnomAD4 exome AF: 0.0757 AC: 106903 AN: 1412870 Hom.: 4607 Cov.: 24 AF XY: 0.0743 AC XY: 52247 AN XY: 703602

African (AFR) AF: 0.0128 AC: 415 AN: 32434

American (AMR) AF: 0.0878 AC: 3688 AN: 41988

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 1501 AN: 25518

East Asian (EAS) AF: 0.00803 AC: 315 AN: 39230

South Asian (SAS) AF: 0.0292 AC: 2451 AN: 83856

European-Finnish (FIN) AF: 0.0907 AC: 4791 AN: 52812

Middle Eastern (MID) AF: 0.0145 AC: 82 AN: 5674

European-Non Finnish (NFE) AF: 0.0839 AC: 89955 AN: 1072630

Other (OTH) AF: 0.0631 AC: 3705 AN: 58728

GnomAD4 genome AF: 0.0559 AC: 8509 AN: 152122 Hom.: 327 Cov.: 32 AF XY: 0.0552 AC XY: 4101 AN XY: 74360

African (AFR) AF: 0.0150 AC: 623 AN: 41526

American (AMR) AF: 0.0598 AC: 915 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3468

East Asian (EAS) AF: 0.00946 AC: 49 AN: 5178

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4814

European-Finnish (FIN) AF: 0.0929 AC: 982 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0796 AC: 5410 AN: 67954

Other (OTH) AF: 0.0530 AC: 112 AN: 2112

Alfa AF: 0.0396 Hom.: 40

Bravo AF: 0.0542

Asia WGS AF: 0.0230 AC: 82 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.43
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: rs12434245; hg19: chr14-64691853;