chr14-64186428-T-C

Variant names:

• chr14-64186428-T-C
• rs117070973
• NM_182914.3:c.17561T>C

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.17561T>C​(p.Leu5854Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00638 in 1,614,206 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L5854I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (53 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.39
• Publications: 10 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=0.008620858).
• BP6: Variant 14-64186428-T-C is Benign according to our data. Variant chr14-64186428-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 199247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00505 (770/152342) while in subpopulation NFE AF = 0.00817 (556/68028). AF 95% confidence interval is 0.00761. There are 3 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 770 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.17561T>C	p.Leu5854Pro	missense	Exon 97 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.17561T>C	p.Leu5854Pro	missense	Exon 97 of 115	NP_055995.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.17561T>C	p.Leu5854Pro	missense	Exon 97 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.17561T>C	p.Leu5854Pro	missense	Exon 97 of 115	ENSP00000341781.4
	SYNE2	ENST00000394768.6	TSL:1	n.7094T>C		non_coding_transcript_exon	Exon 45 of 63

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152224 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00817

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00515 AC: 1296 AN: 251496 AF XY: 0.00507

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.00773

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00651 AC: 9524 AN: 1461864 Hom.: 53 Cov.: 32 AF XY: 0.00636 AC XY: 4622 AN XY: 727244

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00181 AC: 81 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26134

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

South Asian (SAS) AF: 0.00270 AC: 233 AN: 86256

European-Finnish (FIN) AF: 0.00983 AC: 525 AN: 53416

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00749 AC: 8325 AN: 1111996

Other (OTH) AF: 0.00487 AC: 294 AN: 60390

GnomAD4 genome AF: 0.00505 AC: 770 AN: 152342 Hom.: 3 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74492

African (AFR) AF: 0.00113 AC: 47 AN: 41578

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00923 AC: 98 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00817 AC: 556 AN: 68028

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00623 Hom.: 7

Bravo AF: 0.00388

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00574 AC: 697

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00658

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.59
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.85
MVP		0.63
MPC		0.39
ClinPred		0.034	T
GERP RS		5.7
Varity_R		0.91
gMVP		0.70
Mutation Taster		=93/7	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: rs117070973; hg19: chr14-64653146; COSMIC: COSV59951050;