rs1255912

Variant names:

• chr14-63995289-A-C
• rs1255912
• NM_182914.3:c.2940+87A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):​c.2940+87A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,239,140 control chromosomes in the GnomAD database, including 133,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21637 hom., cov: 32)
  • Exomes 𝑓: 0.45 (111910 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.402
• Publications: 5 publications found

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]

SYNE2 Gene-Disease associations (from GenCC):

• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Emery-Dreifuss muscular dystrophy 5, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-63995289-A-C is Benign according to our data. Variant chr14-63995289-A-C is described in ClinVar as Benign. ClinVar VariationId is 1246447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.2940+87A>C		intron_variant	Intron 23 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.2940+87A>C		intron_variant	Intron 23 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79066 AN: 151854 Hom.: 21618 Cov.: 32

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.498

GnomAD4 exome AF: 0.451 AC: 489903 AN: 1087168 Hom.: 111910 AF XY: 0.448 AC XY: 247793 AN XY: 552650

African (AFR) AF: 0.711 AC: 17966 AN: 25282

American (AMR) AF: 0.460 AC: 16942 AN: 36846

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 10896 AN: 22088

East Asian (EAS) AF: 0.551 AC: 19667 AN: 35694

South Asian (SAS) AF: 0.425 AC: 31512 AN: 74220

European-Finnish (FIN) AF: 0.416 AC: 19230 AN: 46218

Middle Eastern (MID) AF: 0.507 AC: 2443 AN: 4816

European-Non Finnish (NFE) AF: 0.439 AC: 349259 AN: 795264

Other (OTH) AF: 0.470 AC: 21988 AN: 46740

GnomAD4 genome AF: 0.521 AC: 79138 AN: 151972 Hom.: 21637 Cov.: 32 AF XY: 0.515 AC XY: 38274 AN XY: 74274

African (AFR) AF: 0.699 AC: 28953 AN: 41446

American (AMR) AF: 0.470 AC: 7175 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 1646 AN: 3470

East Asian (EAS) AF: 0.528 AC: 2731 AN: 5170

South Asian (SAS) AF: 0.446 AC: 2150 AN: 4820

European-Finnish (FIN) AF: 0.412 AC: 4347 AN: 10540

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.448 AC: 30405 AN: 67944

Other (OTH) AF: 0.499 AC: 1052 AN: 2108

Alfa AF: 0.490 Hom.: 2441

Bravo AF: 0.537

Asia WGS AF: 0.503 AC: 1746 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.5
DANN	Benign	0.41
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1255912; hg19: chr14-64462007;