chr14-64225747-T-C

Variant names:

• chr14-64225747-T-C
• rs1048315
• ENST00000394768.6:n.10412T>C

Variant summary

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

The ENST00000394768.6(SYNE2):​n.10412T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 610,564 control chromosomes in the GnomAD database, including 14,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6986 hom., cov: 32)
  • Exomes 𝑓: 0.14 (7213 hom.)
• Consequence: SYNE2 ENST00000394768.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.250
• Publications: 12 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=-0.86).
• BP6: Variant 14-64225747-T-C is Benign according to our data. Variant chr14-64225747-T-C is described in ClinVar as Benign. ClinVar VariationId is 313677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.*221T>C		3_prime_UTR_variant	Exon 116 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.*221T>C		3_prime_UTR_variant	Exon 116 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36203 AN: 152090 Hom.: 6977 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0992

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.144 AC: 65985 AN: 458356 Hom.: 7213 Cov.: 4 AF XY: 0.143 AC XY: 34522 AN XY: 240880

African (AFR) AF: 0.515 AC: 6566 AN: 12752

American (AMR) AF: 0.132 AC: 2703 AN: 20498

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 2130 AN: 14122

East Asian (EAS) AF: 0.391 AC: 12159 AN: 31064

South Asian (SAS) AF: 0.159 AC: 7476 AN: 47152

European-Finnish (FIN) AF: 0.109 AC: 3337 AN: 30594

Middle Eastern (MID) AF: 0.143 AC: 286 AN: 2002

European-Non Finnish (NFE) AF: 0.0987 AC: 27013 AN: 273824

Other (OTH) AF: 0.164 AC: 4315 AN: 26348

GnomAD4 genome AF: 0.238 AC: 36256 AN: 152208 Hom.: 6986 Cov.: 32 AF XY: 0.238 AC XY: 17696 AN XY: 74426

African (AFR) AF: 0.519 AC: 21522 AN: 41504

American (AMR) AF: 0.164 AC: 2514 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 500 AN: 3472

East Asian (EAS) AF: 0.464 AC: 2397 AN: 5170

South Asian (SAS) AF: 0.167 AC: 806 AN: 4816

European-Finnish (FIN) AF: 0.117 AC: 1239 AN: 10620

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0992 AC: 6744 AN: 68006

Other (OTH) AF: 0.208 AC: 440 AN: 2116

Alfa AF: 0.143 Hom.: 10858

Bravo AF: 0.254

Asia WGS AF: 0.296 AC: 1027 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.0
DANN	Benign	0.52
PhyloP100		0.25
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: rs1048315; hg19: chr14-64692465;