14-63852971-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000674003.1(SYNE2):c.-52+218C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 151,768 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (43 hom., cov: 32)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: SYNE2 ENST00000674003.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.186

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 14-63852971-C-T is Benign according to our data. Variant chr14-63852971-C-T is described in ClinVar as [Benign]. Clinvar id is 313475.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0209 (3164/151390) while in subpopulation AMR AF= 0.0337 (513/15220). AF 95% confidence interval is 0.0313. There are 43 homozygotes in gnomad4. There are 1574 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3			upstream_gene_variant		ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6			upstream_gene_variant		1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3150 AN: 151280 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00908

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.0344

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.00540

Gnomad MID AF: 0.0290

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0303

GnomAD4 exome AF: 0.0556 AC: 21 AN: 378 Hom.: 0 Cov.: 0 AF XY: 0.0647 AC XY: 18 AN XY: 278

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0469

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0536

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.0209 AC: 3164 AN: 151390 Hom.: 43 Cov.: 32 AF XY: 0.0213 AC XY: 1574 AN XY: 73990

Gnomad4 AFR AF: 0.00940

Gnomad4 AMR AF: 0.0337

Gnomad4 ASJ AF: 0.0344

Gnomad4 EAS AF: 0.000587

Gnomad4 SAS AF: 0.0332

Gnomad4 FIN AF: 0.00540

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0310

Alfa AF: 0.0228 Hom.: 7

Bravo AF: 0.0207

Asia WGS AF: 0.0240 AC: 81 AN: 3348

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	15
Dann	Uncertain	0.98

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143315154; hg19: chr14-64319689;