rs17766354

Variant names:

• chr14-64137874-C-G
• rs17766354
• NM_182914.3:c.14734C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-64137874-C-G
• chr14-64137874-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):​c.14734C>G​(p.Pro4912Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,614,114 control chromosomes in the GnomAD database, including 1,243 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (146 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1097 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.01
• Publications: 15 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=0.0024898648).
• BP6: Variant 14-64137874-C-G is Benign according to our data. Variant chr14-64137874-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

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.14734C>G	p.Pro4912Ala	missense	Exon 79 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.14734C>G	p.Pro4912Ala	missense	Exon 79 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.14734C>G	p.Pro4912Ala	missense	Exon 79 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.14734C>G	p.Pro4912Ala	missense	Exon 79 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000394768.6	TSL:1	n.4267C>G		non_coding_transcript_exon	Exon 27 of 63

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5827 AN: 152116 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0494

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.0329 AC: 8259 AN: 251326 AF XY: 0.0323

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000925

Gnomad FIN exome AF: 0.0485

Gnomad NFE exome AF: 0.0424

Gnomad OTH exome AF: 0.0424

GnomAD4 exome AF: 0.0365 AC: 53327 AN: 1461880 Hom.: 1097 Cov.: 31 AF XY: 0.0360 AC XY: 26165 AN XY: 727240

African (AFR) AF: 0.0457 AC: 1531 AN: 33480

American (AMR) AF: 0.0222 AC: 994 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 737 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0135 AC: 1166 AN: 86258

European-Finnish (FIN) AF: 0.0459 AC: 2450 AN: 53420

Middle Eastern (MID) AF: 0.0673 AC: 388 AN: 5768

European-Non Finnish (NFE) AF: 0.0395 AC: 43901 AN: 1111998

Other (OTH) AF: 0.0356 AC: 2149 AN: 60396

GnomAD4 genome AF: 0.0383 AC: 5828 AN: 152234 Hom.: 146 Cov.: 32 AF XY: 0.0381 AC XY: 2833 AN XY: 74426

African (AFR) AF: 0.0411 AC: 1706 AN: 41522

American (AMR) AF: 0.0340 AC: 520 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5182

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4824

European-Finnish (FIN) AF: 0.0494 AC: 524 AN: 10600

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0396 AC: 2695 AN: 68026

Other (OTH) AF: 0.0394 AC: 83 AN: 2108

Alfa AF: 0.0345 Hom.: 91

Bravo AF: 0.0380

TwinsUK AF: 0.0356 AC: 132

ALSPAC AF: 0.0397 AC: 153

ESP6500AA AF: 0.0397 AC: 175

ESP6500EA AF: 0.0378 AC: 325

ExAC AF: 0.0330 AC: 4003

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0419

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.0
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.071
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.013	D
Polyphen		0.90	P
Vest4		0.19
MPC		0.18
ClinPred		0.040	T
GERP RS		4.0
Varity_R		0.17
gMVP		0.099
Mutation Taster		=97/3	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: rs17766354; hg19: chr14-64604592;