rs17179194

Variant names:

• chr14-64167266-G-A
• rs17179194
• NM_182914.3:c.16639G>A

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.16639G>A​(p.Asp5547Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0137 in 1,614,194 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D5547G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (212 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.65
• Publications: 8 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=0.0024761856).
• BP6: Variant 14-64167266-G-A is Benign according to our data. Variant chr14-64167266-G-A is described in ClinVar as Benign. ClinVar VariationId is 313627.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 (1594/152318) while in subpopulation SAS AF = 0.0228 (110/4824). AF 95% confidence interval is 0.0193. There are 13 homozygotes in GnomAd4. There are 713 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1594 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.16639G>A	p.Asp5547Asn	missense	Exon 91 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.16639G>A	p.Asp5547Asn	missense	Exon 91 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.16639G>A	p.Asp5547Asn	missense	Exon 91 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.16639G>A	p.Asp5547Asn	missense	Exon 91 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000394768.6	TSL:1	n.6172G>A		non_coding_transcript_exon	Exon 39 of 63

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1593 AN: 152200 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.0449

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0132 AC: 3312 AN: 251298 AF XY: 0.0143

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.0457

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0140 AC: 20453 AN: 1461876 Hom.: 212 Cov.: 30 AF XY: 0.0145 AC XY: 10536 AN XY: 727242

African (AFR) AF: 0.00236 AC: 79 AN: 33480

American (AMR) AF: 0.00642 AC: 287 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0460 AC: 1203 AN: 26136

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

South Asian (SAS) AF: 0.0255 AC: 2201 AN: 86254

European-Finnish (FIN) AF: 0.00328 AC: 175 AN: 53418

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5768

European-Non Finnish (NFE) AF: 0.0140 AC: 15541 AN: 1112000

Other (OTH) AF: 0.0144 AC: 872 AN: 60396

GnomAD4 genome AF: 0.0105 AC: 1594 AN: 152318 Hom.: 13 Cov.: 32 AF XY: 0.00957 AC XY: 713 AN XY: 74478

African (AFR) AF: 0.00385 AC: 160 AN: 41576

American (AMR) AF: 0.00758 AC: 116 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0449 AC: 156 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4824

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0141 AC: 960 AN: 68032

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0143 Hom.: 105

Bravo AF: 0.0105

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0132 AC: 1597

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0160

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	0.093
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.7
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.78	P
Vest4		0.13
MPC		0.050
ClinPred		0.052	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.24
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17179194; hg19: chr14-64633984;