NM_182914.3:c.19857G>T

Variant names:

• chr14-64219407-G-T
• rs35648226
• NM_182914.3:c.19857G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182914.3(SYNE2):​c.19857G>T​(p.Leu6619Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,108 control chromosomes in the GnomAD database, including 58,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4771 hom., cov: 31)
  • Exomes 𝑓: 0.27 (54029 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.932
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 14-64219407-G-T is Benign according to our data. Variant chr14-64219407-G-T is described in ClinVar as Benign. ClinVar VariationId is 130490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.932 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 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.19857G>T	p.Leu6619Leu	synonymous	Exon 110 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.19788G>T	p.Leu6596Leu	synonymous	Exon 109 of 115	NP_055995.4
	SYNE2	NM_182913.4		c.759G>T	p.Leu253Leu	synonymous	Exon 5 of 11	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.19857G>T	p.Leu6619Leu	synonymous	Exon 110 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.19788G>T	p.Leu6596Leu	synonymous	Exon 109 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000458046.6	TSL:1	c.759G>T	p.Leu253Leu	synonymous	Exon 5 of 11	ENSP00000391937.2	Q8WXH0-5

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37223 AN: 151888 Hom.: 4775 Cov.: 31

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.236 AC: 59290 AN: 250938 AF XY: 0.243

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.0964

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.267 AC: 390347 AN: 1461102 Hom.: 54029 Cov.: 36 AF XY: 0.267 AC XY: 194226 AN XY: 726894

African (AFR) AF: 0.207 AC: 6921 AN: 33476

American (AMR) AF: 0.144 AC: 6445 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8652 AN: 26132

East Asian (EAS) AF: 0.111 AC: 4406 AN: 39698

South Asian (SAS) AF: 0.255 AC: 22015 AN: 86226

European-Finnish (FIN) AF: 0.229 AC: 12234 AN: 53340

Middle Eastern (MID) AF: 0.280 AC: 1615 AN: 5768

European-Non Finnish (NFE) AF: 0.281 AC: 312101 AN: 1111378

Other (OTH) AF: 0.264 AC: 15958 AN: 60370

GnomAD4 genome AF: 0.245 AC: 37228 AN: 152006 Hom.: 4771 Cov.: 31 AF XY: 0.240 AC XY: 17838 AN XY: 74284

African (AFR) AF: 0.211 AC: 8761 AN: 41444

American (AMR) AF: 0.205 AC: 3128 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3472

East Asian (EAS) AF: 0.110 AC: 571 AN: 5178

South Asian (SAS) AF: 0.254 AC: 1219 AN: 4802

European-Finnish (FIN) AF: 0.221 AC: 2335 AN: 10566

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19048 AN: 67950

Other (OTH) AF: 0.259 AC: 547 AN: 2110

Alfa AF: 0.263 Hom.: 4347

Bravo AF: 0.240

Asia WGS AF: 0.199 AC: 695 AN: 3478

EpiCase AF: 0.288

EpiControl AF: 0.291

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)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.60
DANN	Benign	0.57
PhyloP100		0.93
Mutation Taster		=97/3	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: rs35648226; hg19: chr14-64686125; COSMIC: COSV59952669; COSMIC: COSV59952669;