14-64098818-C-T

Variant names:

• chr14-64098818-C-T
• rs36007735
• NM_182914.3:c.12378C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_182914.3(SYNE2):​c.12378C>T​(p.Ser4126Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 1,613,616 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (47 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.711
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-64098818-C-T is Benign according to our data. Variant chr14-64098818-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.711 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00517 (787/152086) while in subpopulation NFE AF = 0.00784 (533/67988). AF 95% confidence interval is 0.00729. There are 5 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 787 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.12378C>T	p.Ser4126Ser	synonymous	Exon 63 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.12378C>T	p.Ser4126Ser	synonymous	Exon 63 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.12378C>T	p.Ser4126Ser	synonymous	Exon 63 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.12378C>T	p.Ser4126Ser	synonymous	Exon 63 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000394768.6	TSL:1	n.1911C>T		non_coding_transcript_exon	Exon 11 of 63

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 151968 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00596

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00782

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00546 AC: 1371 AN: 251134 AF XY: 0.00557

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00726

Gnomad NFE exome AF: 0.00752

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00693 AC: 10135 AN: 1461530 Hom.: 47 Cov.: 31 AF XY: 0.00688 AC XY: 4999 AN XY: 727054

African (AFR) AF: 0.00146 AC: 49 AN: 33472

American (AMR) AF: 0.00226 AC: 101 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 431 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00203 AC: 175 AN: 86168

European-Finnish (FIN) AF: 0.00801 AC: 428 AN: 53400

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.00764 AC: 8490 AN: 1111814

Other (OTH) AF: 0.00633 AC: 382 AN: 60382

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152086 Hom.: 5 Cov.: 32 AF XY: 0.00496 AC XY: 369 AN XY: 74346

African (AFR) AF: 0.00154 AC: 64 AN: 41474

American (AMR) AF: 0.00255 AC: 39 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4816

European-Finnish (FIN) AF: 0.00596 AC: 63 AN: 10562

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

European-Non Finnish (NFE) AF: 0.00784 AC: 533 AN: 67988

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00743 Hom.: 2

Bravo AF: 0.00469

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00829

EpiControl AF: 0.00831

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.89
DANN	Benign	0.68
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.050		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: rs36007735; hg19: chr14-64565536; COSMIC: COSV59967064; COSMIC: COSV59967064;