chr14-64210033-C-T

Variant names:

• chr14-64210033-C-T
• rs36215895
• NM_182914.3:c.18632C>T

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.18632C>T​(p.Thr6211Met) variant causes a missense change. The variant allele was found at a frequency of 0.00695 in 1,614,120 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T6211A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (57 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 4.72
• Publications: 16 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 (MetaRNN=0.00664407).
• BP6: Variant 14-64210033-C-T is Benign according to our data. Variant chr14-64210033-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2324.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 = 0.00403 (614/152312) while in subpopulation NFE AF = 0.0066 (449/68026). AF 95% confidence interval is 0.0061. There are 3 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 614 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.18632C>T	p.Thr6211Met	missense	Exon 103 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.18632C>T	p.Thr6211Met	missense	Exon 103 of 115	NP_055995.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.18632C>T	p.Thr6211Met	missense	Exon 103 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.18632C>T	p.Thr6211Met	missense	Exon 103 of 115	ENSP00000341781.4
	SYNE2	ENST00000394768.6	TSL:1	n.8165C>T		non_coding_transcript_exon	Exon 51 of 63

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152194 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00658

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00476 AC: 1195 AN: 250900 AF XY: 0.00474

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00658

Gnomad NFE exome AF: 0.00766

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00725 AC: 10598 AN: 1461808 Hom.: 57 Cov.: 32 AF XY: 0.00702 AC XY: 5104 AN XY: 727216

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00172 AC: 77 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00111 AC: 96 AN: 86258

European-Finnish (FIN) AF: 0.00666 AC: 355 AN: 53334

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00864 AC: 9605 AN: 1112012

Other (OTH) AF: 0.00515 AC: 311 AN: 60396

GnomAD4 genome AF: 0.00403 AC: 614 AN: 152312 Hom.: 3 Cov.: 33 AF XY: 0.00360 AC XY: 268 AN XY: 74460

African (AFR) AF: 0.00130 AC: 54 AN: 41578

American (AMR) AF: 0.00150 AC: 23 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00475 Hom.: 4

Bravo AF: 0.00385

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00503 AC: 611

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00747

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.035	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.7
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.37
MVP		0.48
MPC		0.28
ClinPred		0.063	T
GERP RS		4.7
Varity_R		0.30
gMVP		0.16
Mutation Taster		=90/10	polymorphism

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: rs36215895; hg19: chr14-64676751;