rs768588312

chr14-63990570-GTC-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BS1 BS2

The NM_182914.3(SYNE2):c.2472+7_2472+8del variant causes a splice donor, splice donor region, intron change. The variant allele was found at a frequency of 0.0000223 in 1,613,198 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: SYNE2 NM_182914.3 splice_donor, splice_donor_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.88

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 -8 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.007624011 fraction of the gene. Cryptic splice site detected, with MaxEntScore 1.1, offset of 0 (no position change), new splice context is: cagGTctct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 14-63990570-GTC-G is Benign according to our data. Variant chr14-63990570-GTC-G is described in ClinVar as [Likely_benign]. Clinvar id is 470969.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000131 (2/152188) while in subpopulation EAS AF= 0.000384 (2/5204). AF 95% confidence interval is 0.000068. There are 0 homozygotes in gnomad4. There are 0 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.2472+7_2472+8del		splice_donor_variant, splice_donor_region_variant, intron_variant		ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.2472+7_2472+8del		splice_donor_variant, splice_donor_region_variant, intron_variant		1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249458 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461010 Hom.: 1 AF XY: 0.0000193 AC XY: 14 AN XY: 726854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000384

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.00260 AC: 9 AN: 3478

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs768588312; hg19: chr14-64457288;