rs1152590

Variant names:

• chr14-64214475-C-T
• rs1152590
• NM_182914.3:c.19333+5C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-64214475-C-T
• chr14-64214475-C-A
• chr14-64214475-C-G

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.19333+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,607,706 control chromosomes in the GnomAD database, including 141,801 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 0.50 (21508 hom., cov: 31)
  • Exomes 𝑓: 0.40 (120293 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002039
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.20
• Publications: 14 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=-0.9).
• BP6: Variant 14-64214475-C-T is Benign according to our data. Variant chr14-64214475-C-T is described in ClinVar as Benign. ClinVar VariationId is 130489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.19333+5C>T		splice_region intron	N/A	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.19333+5C>T		splice_region intron	N/A	NP_055995.4
	SYNE2	NM_182913.4		c.235+5C>T		splice_region intron	N/A	NP_878917.1	Q8WXH0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.19333+5C>T		splice_region intron	N/A	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.19333+5C>T		splice_region intron	N/A	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000458046.6	TSL:1	c.235+5C>T		splice_region intron	N/A	ENSP00000391937.2	Q8WXH0-5

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76403 AN: 151780 Hom.: 21470 Cov.: 31

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.491

GnomAD2 exomes AF: 0.441 AC: 105741 AN: 239802 AF XY: 0.432

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.398 AC: 579038 AN: 1455808 Hom.: 120293 Cov.: 38 AF XY: 0.397 AC XY: 287683 AN XY: 724044

African (AFR) AF: 0.768 AC: 25660 AN: 33406

American (AMR) AF: 0.393 AC: 17340 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 12680 AN: 26076

East Asian (EAS) AF: 0.650 AC: 25728 AN: 39598

South Asian (SAS) AF: 0.427 AC: 36719 AN: 85934

European-Finnish (FIN) AF: 0.366 AC: 18809 AN: 51332

Middle Eastern (MID) AF: 0.452 AC: 2305 AN: 5104

European-Non Finnish (NFE) AF: 0.373 AC: 413626 AN: 1110090

Other (OTH) AF: 0.435 AC: 26171 AN: 60164

GnomAD4 genome AF: 0.504 AC: 76493 AN: 151898 Hom.: 21508 Cov.: 31 AF XY: 0.501 AC XY: 37161 AN XY: 74222

African (AFR) AF: 0.758 AC: 31390 AN: 41438

American (AMR) AF: 0.424 AC: 6478 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1684 AN: 3468

East Asian (EAS) AF: 0.695 AC: 3574 AN: 5142

South Asian (SAS) AF: 0.447 AC: 2146 AN: 4804

European-Finnish (FIN) AF: 0.366 AC: 3862 AN: 10550

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25734 AN: 67910

Other (OTH) AF: 0.487 AC: 1028 AN: 2110

Alfa AF: 0.434 Hom.: 8110

Bravo AF: 0.520

Asia WGS AF: 0.549 AC: 1907 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.66
DANN	Benign	0.74
PhyloP100		-1.2
PromoterAI		-0.020	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
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: rs1152590; hg19: chr14-64681193; COSMIC: COSV107422213; COSMIC: COSV107422213;