chr14-64113357-T-C

Variant names:

• chr14-64113357-T-C
• rs61747118
• NM_182914.3:c.12626T>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.12626T>C​(p.Ile4209Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,613,922 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I4209V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (48 hom., cov: 32)
  • Exomes 𝑓: 0.017 (230 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.468
• Publications: 9 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=0.002542466).
• BP6: Variant 14-64113357-T-C is Benign according to our data. Variant chr14-64113357-T-C is described in ClinVar as Benign. ClinVar VariationId is 130467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0226 (3443/152272) while in subpopulation AFR AF = 0.0374 (1556/41556). AF 95% confidence interval is 0.0359. There are 48 homozygotes in GnomAd4. There are 1705 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3443 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.12626T>C	p.Ile4209Thr	missense	Exon 66 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.12626T>C	p.Ile4209Thr	missense	Exon 66 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.12626T>C	p.Ile4209Thr	missense	Exon 66 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.12626T>C	p.Ile4209Thr	missense	Exon 66 of 115	ENSP00000341781.4
	SYNE2	ENST00000394768.6	TSL:1	n.2159T>C		non_coding_transcript_exon	Exon 14 of 63

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3434 AN: 152154 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0168 AC: 4228 AN: 251444 AF XY: 0.0172

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0166 AC: 24251 AN: 1461650 Hom.: 230 Cov.: 32 AF XY: 0.0167 AC XY: 12135 AN XY: 727112

African (AFR) AF: 0.0385 AC: 1289 AN: 33466

American (AMR) AF: 0.00780 AC: 349 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 482 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39698

South Asian (SAS) AF: 0.0220 AC: 1900 AN: 86244

European-Finnish (FIN) AF: 0.0258 AC: 1376 AN: 53416

Middle Eastern (MID) AF: 0.0242 AC: 135 AN: 5588

European-Non Finnish (NFE) AF: 0.0158 AC: 17540 AN: 1112006

Other (OTH) AF: 0.0193 AC: 1168 AN: 60372

GnomAD4 genome AF: 0.0226 AC: 3443 AN: 152272 Hom.: 48 Cov.: 32 AF XY: 0.0229 AC XY: 1705 AN XY: 74460

African (AFR) AF: 0.0374 AC: 1556 AN: 41556

American (AMR) AF: 0.0189 AC: 289 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4824

European-Finnish (FIN) AF: 0.0285 AC: 302 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1039 AN: 68006

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0163 Hom.: 83

Bravo AF: 0.0222

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.0347 AC: 153

ESP6500EA AF: 0.0158 AC: 136

ExAC AF: 0.0171 AC: 2075

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0138

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.3
DANN	Benign	0.52
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.47
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.076
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.0040	B
Vest4		0.13
MPC		0.058
ClinPred		0.0025	T
GERP RS		2.0
PromoterAI		0.026	Neutral
Varity_R		0.040
gMVP		0.11
Mutation Taster		=100/0	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: rs61747118; hg19: chr14-64580075;