NM_182914.3:c.11485-123G>A

Variant names:

• chr14-64087548-G-A
• rs72720309
• NM_182914.3:c.11485-123G>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.11485-123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0798 in 1,045,970 control chromosomes in the GnomAD database, including 3,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (987 hom., cov: 32)
  • Exomes 𝑓: 0.075 (2874 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.890
• Publications: 2 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=-0.92).
• BP6: Variant 14-64087548-G-A is Benign according to our data. Variant chr14-64087548-G-A is described in ClinVar as [Benign]. Clinvar id is 1274614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.11485-123G>A		intron_variant	Intron 57 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.11485-123G>A		intron_variant	Intron 57 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15902 AN: 151944 Hom.: 979 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0843

Gnomad EAS AF: 0.0501

Gnomad SAS AF: 0.0618

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0741

Gnomad OTH AF: 0.0977

GnomAD4 exome AF: 0.0755 AC: 67484 AN: 893908 Hom.: 2874 Cov.: 12 AF XY: 0.0747 AC XY: 34962 AN XY: 468308

African (AFR) AF: 0.176 AC: 3930 AN: 22324

American (AMR) AF: 0.118 AC: 5120 AN: 43364

Ashkenazi Jewish (ASJ) AF: 0.0785 AC: 1758 AN: 22400

East Asian (EAS) AF: 0.0534 AC: 1962 AN: 36772

South Asian (SAS) AF: 0.0601 AC: 4425 AN: 73648

European-Finnish (FIN) AF: 0.0758 AC: 3906 AN: 51518

Middle Eastern (MID) AF: 0.0906 AC: 421 AN: 4648

European-Non Finnish (NFE) AF: 0.0714 AC: 42653 AN: 597682

Other (OTH) AF: 0.0796 AC: 3309 AN: 41552

GnomAD4 genome AF: 0.105 AC: 15958 AN: 152062 Hom.: 987 Cov.: 32 AF XY: 0.105 AC XY: 7821 AN XY: 74340

African (AFR) AF: 0.171 AC: 7097 AN: 41460

American (AMR) AF: 0.112 AC: 1709 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0843 AC: 292 AN: 3464

East Asian (EAS) AF: 0.0500 AC: 259 AN: 5182

South Asian (SAS) AF: 0.0620 AC: 299 AN: 4820

European-Finnish (FIN) AF: 0.0875 AC: 926 AN: 10580

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0741 AC: 5036 AN: 67962

Other (OTH) AF: 0.0995 AC: 210 AN: 2110

Alfa AF: 0.0957 Hom.: 102

Bravo AF: 0.109

Asia WGS AF: 0.0810 AC: 281 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.29
DANN	Benign	0.24
PhyloP100		-0.89
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: rs72720309; hg19: chr14-64554266; COSMIC: COSV59976433;