rs10135310

Positions:

• chr14-64107422-C-A
• chr14-64107422-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):​c.12493-69C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0986 in 1,346,174 control chromosomes in the GnomAD database, including 9,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1739 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7850 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-64107422-C-A is Benign according to our data. Variant chr14-64107422-C-A is described in ClinVar as [Benign]. Clinvar id is 1179269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.12493-69C>A		intron_variant		ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.12493-69C>A		intron_variant		1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20162 AN: 151926 Hom.: 1737 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0730

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.0943 AC: 112553 AN: 1194130 Hom.: 7850 AF XY: 0.0972 AC XY: 58980 AN XY: 606814

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.0961

Gnomad4 NFE exome AF: 0.0659

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.133 AC: 20191 AN: 152044 Hom.: 1739 Cov.: 32 AF XY: 0.139 AC XY: 10319 AN XY: 74342

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0730

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0868 Hom.: 1287

Bravo AF: 0.138

Asia WGS AF: 0.237 AC: 823 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.23
DANN	Benign	0.36

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: rs10135310; hg19: chr14-64574140; COSMIC: COSV59939088;