rs150955173

Variant names:

• chr14-64216260-C-T
• rs150955173
• NM_182914.3:c.19415C>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_182910.2(SYNE2):​c.-62C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00295 in 1,614,206 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (12 hom.)
• Consequence: SYNE2 NM_182910.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.43
• Publications: 9 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=0.0041516125).
• BP6: Variant 14-64216260-C-T is Benign according to our data. Variant chr14-64216260-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282189.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 = 0.00227 (346/152322) while in subpopulation NFE AF = 0.00319 (217/68036). AF 95% confidence interval is 0.00284. There are 2 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 346 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182910.2. 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.19415C>T	p.Ser6472Leu	missense	Exon 108 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_182910.2		c.-62C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_878914.1	Q8WXH0-6
	SYNE2	NM_015180.6		c.19346C>T	p.Ser6449Leu	missense	Exon 107 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.19415C>T	p.Ser6472Leu	missense	Exon 108 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.19346C>T	p.Ser6449Leu	missense	Exon 107 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000458046.6	TSL:1	c.317C>T	p.Ser106Leu	missense	Exon 3 of 11	ENSP00000391937.2	Q8WXH0-5

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00660

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00249 AC: 625 AN: 251460 AF XY: 0.00258

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00712

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00302 AC: 4413 AN: 1461884 Hom.: 12 Cov.: 31 AF XY: 0.00298 AC XY: 2170 AN XY: 727244

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00835 AC: 446 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00337 AC: 3746 AN: 1112010

Other (OTH) AF: 0.00189 AC: 114 AN: 60396

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74484

African (AFR) AF: 0.000457 AC: 19 AN: 41570

American (AMR) AF: 0.00203 AC: 31 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00660 AC: 70 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.00170

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00259 AC: 314

EpiCase AF: 0.00273

EpiControl AF: 0.00290

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0042	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.17
Sift	Benign	0.26	T
Sift4G	Benign	0.12	T
Polyphen		0.97	D
Vest4		0.52
MVP		0.67
MPC		0.23
ClinPred		0.052	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.30
Mutation Taster		=87/13	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: rs150955173; hg19: chr14-64682978; COSMIC: COSV59947759; COSMIC: COSV59947759;