NM_182914.3:c.19639A>G

Variant names:

• chr14-64218494-A-G
• rs45453691
• NM_182914.3:c.19639A>G

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.19639A>G​(p.Ile6547Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,956 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I6547I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 32)
  • Exomes 𝑓: 0.014 (220 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.76
• Publications: 13 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=0.0025786757).
• BP6: Variant 14-64218494-A-G is Benign according to our data. Variant chr14-64218494-A-G is described in ClinVar as Benign. ClinVar VariationId is 313653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0105 (1598/152326) while in subpopulation SAS AF = 0.023 (111/4826). AF 95% confidence interval is 0.0195. There are 15 homozygotes in GnomAd4. There are 730 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1598 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.19639A>G	p.Ile6547Val	missense	Exon 109 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.19570A>G	p.Ile6524Val	missense	Exon 108 of 115	NP_055995.4
	SYNE2	NM_182913.4		c.541A>G	p.Ile181Val	missense	Exon 4 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.19639A>G	p.Ile6547Val	missense	Exon 109 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.19570A>G	p.Ile6524Val	missense	Exon 108 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000458046.6	TSL:1	c.541A>G	p.Ile181Val	missense	Exon 4 of 11	ENSP00000391937.2	Q8WXH0-5

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1598 AN: 152208 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00968

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0136 AC: 3400 AN: 250920 AF XY: 0.0149

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.0428

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00308

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0141 AC: 20569 AN: 1461630 Hom.: 220 Cov.: 31 AF XY: 0.0148 AC XY: 10738 AN XY: 727104

African (AFR) AF: 0.00170 AC: 57 AN: 33480

American (AMR) AF: 0.00686 AC: 307 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 1144 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0281 AC: 2419 AN: 86238

European-Finnish (FIN) AF: 0.00306 AC: 163 AN: 53238

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5768

European-Non Finnish (NFE) AF: 0.0139 AC: 15478 AN: 1111966

Other (OTH) AF: 0.0148 AC: 893 AN: 60390

GnomAD4 genome AF: 0.0105 AC: 1598 AN: 152326 Hom.: 15 Cov.: 32 AF XY: 0.00980 AC XY: 730 AN XY: 74494

African (AFR) AF: 0.00272 AC: 113 AN: 41572

American (AMR) AF: 0.00967 AC: 148 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4826

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 980 AN: 68020

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0150 Hom.: 73

Bravo AF: 0.0107

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0135 AC: 1643

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0163

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.044
DANN	Benign	0.26
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.0040
Sift	Benign	0.47	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.074
MPC		0.042
ClinPred		0.00055	T
GERP RS		-6.5
Varity_R		0.014
gMVP		0.13
Mutation Taster		=99/1	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: rs45453691; hg19: chr14-64685212;