NM_182914.3:c.19964A>T

Variant names:

• chr14-64220540-A-T
• rs149978500
• NM_182914.3:c.19964A>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.19964A>T​(p.Gln6655Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,614,118 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.720
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054953694).
• BP6: Variant 14-64220540-A-T is Benign according to our data. Variant chr14-64220540-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281670.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00192 (293/152224) while in subpopulation NFE AF = 0.003 (204/68008). AF 95% confidence interval is 0.00266. There are 2 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 293 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.19964A>T	p.Gln6655Leu	missense	Exon 111 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.19895A>T	p.Gln6632Leu	missense	Exon 110 of 115	NP_055995.4
	SYNE2	NM_182913.4		c.866A>T	p.Gln289Leu	missense	Exon 6 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.19964A>T	p.Gln6655Leu	missense	Exon 111 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.19895A>T	p.Gln6632Leu	missense	Exon 110 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000458046.6	TSL:1	c.866A>T	p.Gln289Leu	missense	Exon 6 of 11	ENSP00000391937.2	Q8WXH0-5

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152106 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00224 AC: 564 AN: 251454 AF XY: 0.00213

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00306 AC: 4476 AN: 1461894 Hom.: 7 Cov.: 32 AF XY: 0.00310 AC XY: 2252 AN XY: 727248

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

American (AMR) AF: 0.00259 AC: 116 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00562 AC: 147 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86258

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53420

Middle Eastern (MID) AF: 0.0140 AC: 81 AN: 5768

European-Non Finnish (NFE) AF: 0.00341 AC: 3797 AN: 1112012

Other (OTH) AF: 0.00351 AC: 212 AN: 60396

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152224 Hom.: 2 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74416

African (AFR) AF: 0.000530 AC: 22 AN: 41546

American (AMR) AF: 0.00216 AC: 33 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000833 AC: 4 AN: 4802

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00300 AC: 204 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00304 Hom.: 0

Bravo AF: 0.00222

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00222 AC: 270

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.8
DANN	Benign	0.61
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.72
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.075
Sift	Benign	0.043	D
Sift4G	Uncertain	0.043	D
Polyphen		0.31	B
Vest4		0.38
MVP		0.52
MPC		0.14
ClinPred		0.059	T
GERP RS		2.4
Varity_R		0.20
gMVP		0.46
Mutation Taster		=95/5	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: rs149978500; hg19: chr14-64687258; COSMIC: COSV99051080; COSMIC: COSV99051080;