rs1255953

Positions:

• chr14-64084970-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000555002.6(SYNE2):​c.11485-2701C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 702,064 control chromosomes in the GnomAD database, including 226,313 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (42677 hom., cov: 32)
  • Exomes 𝑓: 0.81 (183636 hom.)
• Consequence: SYNE2 ENST00000555002.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.196

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.773652E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.11485-2701C>T		intron_variant		ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.11485-2701C>T		intron_variant		1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111430 AN: 152068 Hom.: 42668 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.807

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.741

GnomAD3 exomes AF: 0.793 AC: 101450 AN: 128008 Hom.: 40735 AF XY: 0.796 AC XY: 55795 AN XY: 70098

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.753

Gnomad SAS exome AF: 0.779

Gnomad FIN exome AF: 0.815

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.777

GnomAD4 exome AF: 0.813 AC: 447277 AN: 549878 Hom.: 183636 Cov.: 0 AF XY: 0.814 AC XY: 242174 AN XY: 297686

Gnomad4 AFR exome AF: 0.481

Gnomad4 AMR exome AF: 0.804

Gnomad4 ASJ exome AF: 0.731

Gnomad4 EAS exome AF: 0.780

Gnomad4 SAS exome AF: 0.783

Gnomad4 FIN exome AF: 0.822

Gnomad4 NFE exome AF: 0.847

Gnomad4 OTH exome AF: 0.791

GnomAD4 genome AF: 0.732 AC: 111467 AN: 152186 Hom.: 42677 Cov.: 32 AF XY: 0.731 AC XY: 54388 AN XY: 74396

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.774

Gnomad4 ASJ AF: 0.737

Gnomad4 EAS AF: 0.774

Gnomad4 SAS AF: 0.771

Gnomad4 FIN AF: 0.807

Gnomad4 NFE AF: 0.851

Gnomad4 OTH AF: 0.740

Alfa AF: 0.821 Hom.: 71360

Bravo AF: 0.720

TwinsUK AF: 0.861 AC: 3194

ALSPAC AF: 0.852 AC: 3282

ExAC AF: 0.738 AC: 9865

Asia WGS AF: 0.744 AC: 2589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.3
DANN	Benign	0.70
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	8.8e-7	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
Sift4G	Benign	0.22	T
Vest4		0.014
ClinPred		0.00010	T
GERP RS		-1.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1255953; hg19: chr14-64551688;