14-64170260-C-T

Variant names:

• chr14-64170260-C-T
• rs147365925
• NM_182914.3:c.17033C>T

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.17033C>T​(p.Thr5678Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. T5678K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.19
• Publications: 2 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=0.009259582).
• BP6: Variant 14-64170260-C-T is Benign according to our data. Variant chr14-64170260-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313629.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 = 0.00088 (134/152304) while in subpopulation AFR AF = 0.00178 (74/41550). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 134 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.17033C>T	p.Thr5678Met	missense	Exon 94 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.17033C>T	p.Thr5678Met	missense	Exon 94 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.17033C>T	p.Thr5678Met	missense	Exon 94 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.17033C>T	p.Thr5678Met	missense	Exon 94 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000394768.6	TSL:1	n.6566C>T		non_coding_transcript_exon	Exon 42 of 63

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000561 AC: 141 AN: 251430 AF XY: 0.000552

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000349 AC: 510 AN: 1461754 Hom.: 0 Cov.: 30 AF XY: 0.000352 AC XY: 256 AN XY: 727176

African (AFR) AF: 0.00158 AC: 53 AN: 33476

American (AMR) AF: 0.00201 AC: 90 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5662

European-Non Finnish (NFE) AF: 0.000277 AC: 308 AN: 1112006

Other (OTH) AF: 0.000878 AC: 53 AN: 60382

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74486

African (AFR) AF: 0.00178 AC: 74 AN: 41550

American (AMR) AF: 0.00144 AC: 22 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68030

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000479 Hom.: 1

Bravo AF: 0.00106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000494 AC: 60

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

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)
-	-	1	not provided (1)
-	-	1	SYNE2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		0.98	D
Vest4		0.23
MVP		0.26
MPC		0.14
ClinPred		0.064	T
GERP RS		-6.3
Varity_R		0.019
gMVP		0.16
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: rs147365925; hg19: chr14-64636978; COSMIC: COSV100647644; COSMIC: COSV100647644;