rs145218296

Variant names:

• chr14-64113579-T-C
• rs145218296
• NM_182914.3:c.12840+8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):​c.12840+8T>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 0.0242 in 1,596,276 control chromosomes in the GnomAD database, including 591 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 (63 hom., cov: 32)
  • Exomes 𝑓: 0.024 (528 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002433
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.35
• 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=-0.84).
• BP6: Variant 14-64113579-T-C is Benign according to our data. Variant chr14-64113579-T-C is described in ClinVar as Benign. ClinVar VariationId is 130468.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 = 0.0222 (3378/152336) while in subpopulation NFE AF = 0.0305 (2077/68024). AF 95% confidence interval is 0.0294. There are 63 homozygotes in GnomAd4. There are 1741 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3378 AD,Unknown 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.12840+8T>C		splice_region intron	N/A	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.12840+8T>C		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.12840+8T>C		splice_region intron	N/A	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.12840+8T>C		splice_region intron	N/A	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000394768.6	TSL:1	n.2373+8T>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3379 AN: 152218 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0615

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0215 AC: 4682 AN: 218112 AF XY: 0.0212

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.00995

Gnomad EAS exome AF: 0.000127

Gnomad FIN exome AF: 0.0543

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0217

GnomAD4 exome AF: 0.0244 AC: 35250 AN: 1443940 Hom.: 528 Cov.: 32 AF XY: 0.0240 AC XY: 17176 AN XY: 716904

African (AFR) AF: 0.00322 AC: 106 AN: 32898

American (AMR) AF: 0.0172 AC: 718 AN: 41846

Ashkenazi Jewish (ASJ) AF: 0.00907 AC: 234 AN: 25810

East Asian (EAS) AF: 0.0000519 AC: 2 AN: 38568

South Asian (SAS) AF: 0.00386 AC: 323 AN: 83576

European-Finnish (FIN) AF: 0.0515 AC: 2688 AN: 52224

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5750

European-Non Finnish (NFE) AF: 0.0271 AC: 29918 AN: 1103474

Other (OTH) AF: 0.0207 AC: 1240 AN: 59794

GnomAD4 genome AF: 0.0222 AC: 3378 AN: 152336 Hom.: 63 Cov.: 32 AF XY: 0.0234 AC XY: 1741 AN XY: 74494

African (AFR) AF: 0.00409 AC: 170 AN: 41590

American (AMR) AF: 0.0265 AC: 406 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.0615 AC: 653 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0305 AC: 2077 AN: 68024

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.0263 Hom.: 23

Bravo AF: 0.0178

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

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)
-	-	1	SYNE2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		-2.4
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0080
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: rs145218296; hg19: chr14-64580297;