rs182079744

Variant names:

• chr14-64202952-G-A
• rs182079744
• NM_182914.3:c.18190G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-64202952-G-A
• chr14-64202952-G-T
• chr14-64202952-G-C

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.18190G>A​(p.Ala6064Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000253 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A6064S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 4.51
• Publications: 2 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=0.015896648).
• BP6: Variant 14-64202952-G-A is Benign according to our data. Variant chr14-64202952-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 313637.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00042 (64/152314) while in subpopulation AMR AF = 0.00176 (27/15300). AF 95% confidence interval is 0.00124. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 64 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.18190G>A	p.Ala6064Thr	missense	Exon 100 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.18190G>A	p.Ala6064Thr	missense	Exon 100 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.18190G>A	p.Ala6064Thr	missense	Exon 100 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.18190G>A	p.Ala6064Thr	missense	Exon 100 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000394768.6	TSL:1	n.7723G>A		non_coding_transcript_exon	Exon 48 of 63

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000274 AC: 69 AN: 251414 AF XY: 0.000280

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000236 AC: 345 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.000230 AC XY: 167 AN XY: 727218

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000203 AC: 226 AN: 1112002

Other (OTH) AF: 0.000464 AC: 28 AN: 60394

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74490

African (AFR) AF: 0.000481 AC: 20 AN: 41568

American (AMR) AF: 0.00176 AC: 27 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68020

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.000612

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	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
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.75	N
PhyloP100		4.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.094
Sift	Benign	0.76	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.18
MVP		0.38
MPC		0.32
ClinPred		0.053	T
GERP RS		5.9
Varity_R		0.056
gMVP		0.14
Mutation Taster		=76/24	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: rs182079744; hg19: chr14-64669670;