NM_182914.3:c.6481C>T

Variant names:

• chr14-64027560-C-T
• rs10151127
• NM_182914.3:c.6481C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182914.3(SYNE2):​c.6481C>T​(p.Leu2161Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.898 in 1,612,324 control chromosomes in the GnomAD database, including 656,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (52057 hom., cov: 33)
  • Exomes 𝑓: 0.91 (604026 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.526
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 14-64027560-C-T is Benign according to our data. Variant chr14-64027560-C-T is described in ClinVar as Benign. ClinVar VariationId is 130503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.526 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.6481C>T	p.Leu2161Leu	synonymous	Exon 43 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.6481C>T	p.Leu2161Leu	synonymous	Exon 43 of 115	NP_055995.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.6481C>T	p.Leu2161Leu	synonymous	Exon 43 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.6481C>T	p.Leu2161Leu	synonymous	Exon 43 of 115	ENSP00000341781.4
	SYNE2	ENST00000358025.7	TSL:5	c.6481C>T	p.Leu2161Leu	synonymous	Exon 43 of 116	ENSP00000350719.3

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123587 AN: 152042 Hom.: 52047 Cov.: 33

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.880

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.822

Gnomad NFE AF: 0.925

Gnomad OTH AF: 0.828

GnomAD2 exomes AF: 0.877 AC: 218492 AN: 249248 AF XY: 0.879

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.930

Gnomad ASJ exome AF: 0.837

Gnomad EAS exome AF: 0.833

Gnomad FIN exome AF: 0.924

Gnomad NFE exome AF: 0.919

Gnomad OTH exome AF: 0.874

GnomAD4 exome AF: 0.907 AC: 1324249 AN: 1460164 Hom.: 604026 Cov.: 38 AF XY: 0.905 AC XY: 657603 AN XY: 726348

African (AFR) AF: 0.534 AC: 17855 AN: 33420

American (AMR) AF: 0.925 AC: 41341 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 21872 AN: 26110

East Asian (EAS) AF: 0.830 AC: 32924 AN: 39664

South Asian (SAS) AF: 0.833 AC: 71590 AN: 85902

European-Finnish (FIN) AF: 0.927 AC: 49507 AN: 53412

Middle Eastern (MID) AF: 0.824 AC: 4732 AN: 5740

European-Non Finnish (NFE) AF: 0.928 AC: 1031480 AN: 1110918

Other (OTH) AF: 0.878 AC: 52948 AN: 60306

GnomAD4 genome AF: 0.813 AC: 123636 AN: 152160 Hom.: 52057 Cov.: 33 AF XY: 0.814 AC XY: 60551 AN XY: 74402

African (AFR) AF: 0.563 AC: 23343 AN: 41474

American (AMR) AF: 0.881 AC: 13471 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 2964 AN: 3470

East Asian (EAS) AF: 0.842 AC: 4356 AN: 5176

South Asian (SAS) AF: 0.822 AC: 3960 AN: 4820

European-Finnish (FIN) AF: 0.927 AC: 9804 AN: 10580

Middle Eastern (MID) AF: 0.818 AC: 239 AN: 292

European-Non Finnish (NFE) AF: 0.925 AC: 62909 AN: 68024

Other (OTH) AF: 0.826 AC: 1747 AN: 2114

Alfa AF: 0.858 Hom.: 25798

Bravo AF: 0.798

Asia WGS AF: 0.810 AC: 2818 AN: 3478

EpiCase AF: 0.916

EpiControl AF: 0.911

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.4
DANN	Benign	0.74
PhyloP100		0.53
Mutation Taster		=299/1	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: rs10151127; hg19: chr14-64494278; COSMIC: COSV108177354;