rs1172418857

Variant names:

• chr14-64087773-TC-T
• rs1172418857
• NM_182914.3:c.11589delC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PVS1 PM2 BP6_Moderate

The NM_182914.3(SYNE2):​c.11589delC​(p.Ile3864TyrfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE2 NM_182914.3 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 14-64087773-TC-T is Benign according to our data. Variant chr14-64087773-TC-T is described in ClinVar as [Likely_benign]. Clinvar id is 1677311.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.11589delC	p.Ile3864TyrfsTer4	frameshift_variant	Exon 58 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.11589delC	p.Ile3864TyrfsTer4	frameshift_variant	Exon 58 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:1

Mar 11, 2022

Breda Genetics srl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant supposedly creates a shift in the reading frame which is predicted to result in a premature stop codon 4 amino acids downstream. However, we have identified this variant in the homozygous state and in a case where other likely pathogenic variants have been detected to explain the pheontype. Notably, the SYNE2 phenotype is associated with autosomal dominant inheritance. We therefore conclude that, depsite being a predicted framshift nucleotide change, this variant is likely benign. There is no information on allele frequency of this variant in gnomAD or 1000 Genomes Project. -

Computational scores

Source: dbNSFP v4.3

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: rs1172418857; hg19: chr14-64554491;