rs141741640

Variant names:

• chr14-64214272-C-T
• rs141741640
• NM_182914.3:c.19135C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182914.3(SYNE2):​c.19135C>T​(p.Arg6379Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,902 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6379H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 0.993
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015034795).
• BP6: Variant 14-64214272-C-T is Benign according to our data. Variant chr14-64214272-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193779.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0013 (198/152008) while in subpopulation NFE AF = 0.00247 (168/67988). AF 95% confidence interval is 0.00217. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 198 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.19135C>T	p.Arg6379Cys	missense	Exon 106 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.19135C>T	p.Arg6379Cys	missense	Exon 106 of 115	NP_055995.4
	SYNE2	NM_182913.4		c.37C>T	p.Arg13Cys	missense	Exon 1 of 11	NP_878917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.19135C>T	p.Arg6379Cys	missense	Exon 106 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.19135C>T	p.Arg6379Cys	missense	Exon 106 of 115	ENSP00000341781.4
	SYNE2	ENST00000458046.6	TSL:1	c.37C>T	p.Arg13Cys	missense	Exon 1 of 11	ENSP00000391937.2

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 151892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000757

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00132 AC: 333 AN: 251488 AF XY: 0.00133

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00188 AC: 2744 AN: 1461894 Hom.: 5 Cov.: 38 AF XY: 0.00178 AC XY: 1292 AN XY: 727248

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00230 AC: 2559 AN: 1112012

Other (OTH) AF: 0.000861 AC: 52 AN: 60396

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74292

African (AFR) AF: 0.000338 AC: 14 AN: 41466

American (AMR) AF: 0.000394 AC: 6 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.000757 AC: 8 AN: 10574

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

European-Non Finnish (NFE) AF: 0.00247 AC: 168 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00186 Hom.: 2

Bravo AF: 0.00127

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00128 AC: 155

EpiCase AF: 0.00240

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (4)
-	1	2	not specified (3)
-	-	2	not provided (2)
-	-	1	SYNE2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.61
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.99
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.083
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.28
MVP		0.52
MPC		0.063
ClinPred		0.067	T
GERP RS		3.5
PromoterAI		-0.0048	Neutral
Varity_R		0.13
gMVP		0.14
Mutation Taster		=71/29	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: rs141741640; hg19: chr14-64680990;