14-64107422-C-A

Variant names:

• chr14-64107422-C-A
• rs10135310
• NM_182914.3:c.12493-69C>A

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.12493-69C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0986 in 1,346,174 control chromosomes in the GnomAD database, including 9,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1739 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7850 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34
• Publications: 6 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=-0.82).
• BP6: Variant 14-64107422-C-A is Benign according to our data. Variant chr14-64107422-C-A is described in ClinVar as Benign. ClinVar VariationId is 1179269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.12493-69C>A		intron_variant	Intron 64 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.12493-69C>A		intron_variant	Intron 64 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20162 AN: 151926 Hom.: 1737 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0730

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.0943 AC: 112553 AN: 1194130 Hom.: 7850 AF XY: 0.0972 AC XY: 58980 AN XY: 606814

African (AFR) AF: 0.200 AC: 5578 AN: 27938

American (AMR) AF: 0.164 AC: 7281 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3083 AN: 24432

East Asian (EAS) AF: 0.340 AC: 13014 AN: 38298

South Asian (SAS) AF: 0.182 AC: 14662 AN: 80712

European-Finnish (FIN) AF: 0.0961 AC: 5060 AN: 52634

Middle Eastern (MID) AF: 0.123 AC: 646 AN: 5240

European-Non Finnish (NFE) AF: 0.0659 AC: 57232 AN: 869102

Other (OTH) AF: 0.116 AC: 5997 AN: 51504

GnomAD4 genome AF: 0.133 AC: 20191 AN: 152044 Hom.: 1739 Cov.: 32 AF XY: 0.139 AC XY: 10319 AN XY: 74342

African (AFR) AF: 0.195 AC: 8097 AN: 41440

American (AMR) AF: 0.161 AC: 2457 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3470

East Asian (EAS) AF: 0.377 AC: 1953 AN: 5174

South Asian (SAS) AF: 0.188 AC: 907 AN: 4822

European-Finnish (FIN) AF: 0.103 AC: 1088 AN: 10554

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0730 AC: 4967 AN: 67996

Other (OTH) AF: 0.131 AC: 276 AN: 2112

Alfa AF: 0.0941 Hom.: 3472

Bravo AF: 0.138

Asia WGS AF: 0.237 AC: 823 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	-0.82
CADD	Benign	0.23
DANN	Benign	0.36
PhyloP100		-1.3
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: rs10135310; hg19: chr14-64574140; COSMIC: COSV59939088;