chr14-64177487-T-C

Variant names:

• chr14-64177487-T-C
• rs2297301
• NM_182914.3:c.17556+4T>C

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.17556+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,614,116 control chromosomes in the GnomAD database, including 974 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (76 hom., cov: 32)
  • Exomes 𝑓: 0.026 (898 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005099
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.265
• 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=-0.77).
• BP6: Variant 14-64177487-T-C is Benign according to our data. Variant chr14-64177487-T-C is described in ClinVar as Benign. ClinVar VariationId is 130487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.17556+4T>C		splice_region intron	N/A	NP_878918.2
	SYNE2	NM_015180.6		c.17556+4T>C		splice_region intron	N/A	NP_055995.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.17556+4T>C		splice_region intron	N/A	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.17556+4T>C		splice_region intron	N/A	ENSP00000341781.4
	SYNE2	ENST00000394768.6	TSL:1	n.7089+4T>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3344 AN: 152180 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0469

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0299 AC: 7512 AN: 251278 AF XY: 0.0305

Gnomad AFR exome AF: 0.00463

Gnomad AMR exome AF: 0.00708

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.0433

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0232

GnomAD4 exome AF: 0.0258 AC: 37747 AN: 1461818 Hom.: 898 Cov.: 32 AF XY: 0.0260 AC XY: 18929 AN XY: 727206

African (AFR) AF: 0.00403 AC: 135 AN: 33480

American (AMR) AF: 0.00850 AC: 380 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 287 AN: 26132

East Asian (EAS) AF: 0.141 AC: 5587 AN: 39684

South Asian (SAS) AF: 0.0375 AC: 3234 AN: 86258

European-Finnish (FIN) AF: 0.0446 AC: 2384 AN: 53412

Middle Eastern (MID) AF: 0.0172 AC: 99 AN: 5768

European-Non Finnish (NFE) AF: 0.0217 AC: 24102 AN: 1111966

Other (OTH) AF: 0.0255 AC: 1539 AN: 60394

GnomAD4 genome AF: 0.0219 AC: 3341 AN: 152298 Hom.: 76 Cov.: 32 AF XY: 0.0232 AC XY: 1730 AN XY: 74482

African (AFR) AF: 0.00467 AC: 194 AN: 41564

American (AMR) AF: 0.0133 AC: 203 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3468

East Asian (EAS) AF: 0.124 AC: 642 AN: 5182

South Asian (SAS) AF: 0.0473 AC: 228 AN: 4818

European-Finnish (FIN) AF: 0.0440 AC: 467 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0221 AC: 1504 AN: 68026

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0221 Hom.: 113

Bravo AF: 0.0195

Asia WGS AF: 0.0780 AC: 269 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0205

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		-0.27
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00051
dbscSNV1_RF	Benign	0.092
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: rs2297301; hg19: chr14-64644205; COSMIC: COSV59952659;