rs117567094

Variant names:

• chr14-63978927-G-A
• rs117567094
• NM_182914.3:c.1482G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_182914.3(SYNE2):​c.1482G>A​(p.Leu494Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 1,612,710 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (86 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.440
• Publications: 4 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
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Emery-Dreifuss muscular dystrophy 5, autosomal dominant

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-63978927-G-A is Benign according to our data. Variant chr14-63978927-G-A is described in ClinVar as Benign. ClinVar VariationId is 313488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00659 (1003/152284) while in subpopulation SAS AF = 0.012 (58/4820). AF 95% confidence interval is 0.00956. There are 9 homozygotes in GnomAd4. There are 499 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1003 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.1482G>A	p.Leu494Leu	synonymous	Exon 14 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.1482G>A	p.Leu494Leu	synonymous	Exon 14 of 115	NP_055995.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.1482G>A	p.Leu494Leu	synonymous	Exon 14 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.1482G>A	p.Leu494Leu	synonymous	Exon 14 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.1482G>A	p.Leu494Leu	synonymous	Exon 14 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 1008 AN: 152166 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.00781 AC: 1948 AN: 249420 AF XY: 0.00891

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00516

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00711

GnomAD4 exome AF: 0.00931 AC: 13590 AN: 1460426 Hom.: 86 Cov.: 30 AF XY: 0.00958 AC XY: 6959 AN XY: 726612

African (AFR) AF: 0.00161 AC: 54 AN: 33448

American (AMR) AF: 0.00228 AC: 102 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0146 AC: 1262 AN: 86216

European-Finnish (FIN) AF: 0.00600 AC: 320 AN: 53352

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5760

European-Non Finnish (NFE) AF: 0.0101 AC: 11237 AN: 1110848

Other (OTH) AF: 0.00792 AC: 478 AN: 60344

GnomAD4 genome AF: 0.00659 AC: 1003 AN: 152284 Hom.: 9 Cov.: 32 AF XY: 0.00670 AC XY: 499 AN XY: 74454

African (AFR) AF: 0.00195 AC: 81 AN: 41562

American (AMR) AF: 0.00569 AC: 87 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4820

European-Finnish (FIN) AF: 0.00538 AC: 57 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 691 AN: 68028

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.00821 Hom.: 4

Bravo AF: 0.00592

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.00942

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.2
DANN	Benign	0.74
PhyloP100		0.44
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117567094; hg19: chr14-64445645; COSMIC: COSV100646345;