rs189611387

Variant names:

• chr14-64202796-T-A
• rs189611387
• NM_182914.3:c.18039-5T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-64202796-T-A
• chr14-64202796-T-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):​c.18039-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,132 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.923
• Publications: 1 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 14-64202796-T-A is Benign according to our data. Variant chr14-64202796-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00198 (301/152254) while in subpopulation NFE AF = 0.00318 (216/68010). AF 95% confidence interval is 0.00283. There are 2 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 301 Unknown,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.18039-5T>A		splice_region intron	N/A	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.18039-5T>A		splice_region intron	N/A	NP_055995.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.18039-5T>A		splice_region intron	N/A	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.18039-5T>A		splice_region intron	N/A	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000394768.6	TSL:1	n.7572-5T>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00235 AC: 590 AN: 251462 AF XY: 0.00226

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00316

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00302 AC: 4419 AN: 1461878 Hom.: 7 Cov.: 32 AF XY: 0.00303 AC XY: 2206 AN XY: 727236

African (AFR) AF: 0.000538 AC: 18 AN: 33478

American (AMR) AF: 0.00259 AC: 116 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00566 AC: 148 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000951 AC: 82 AN: 86258

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53414

Middle Eastern (MID) AF: 0.0147 AC: 85 AN: 5768

European-Non Finnish (NFE) AF: 0.00337 AC: 3748 AN: 1112004

Other (OTH) AF: 0.00329 AC: 199 AN: 60396

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152254 Hom.: 2 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74448

African (AFR) AF: 0.000457 AC: 19 AN: 41550

American (AMR) AF: 0.00203 AC: 31 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00231

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)
-	-	2	not specified (2)
-	-	1	SYNE2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.71
PhyloP100		0.92
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.40		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs189611387; hg19: chr14-64669514;