rs4027402

Variant names:

• chr14-64030031-C-T
• rs4027402
• NM_182914.3:c.6851C>T
• SYNE2 p.Ala2284Val

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.6851C>T​(p.Ala2284Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.849 in 1,613,584 control chromosomes in the GnomAD database, including 591,320 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (44065 hom., cov: 31)
  • Exomes 𝑓: 0.86 (547255 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.370
• Publications: 40 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=1.0792198E-6).
• BP6: Variant 14-64030031-C-T is Benign according to our data. Variant chr14-64030031-C-T is described in ClinVar as Benign. ClinVar VariationId is 130504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.875 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.6851C>T	p.Ala2284Val	missense	Exon 44 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.6851C>T	p.Ala2284Val	missense	Exon 44 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.6851C>T	p.Ala2284Val	missense	Exon 44 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.6851C>T	p.Ala2284Val	missense	Exon 44 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.6851C>T	p.Ala2284Val	missense	Exon 44 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111657 AN: 151870 Hom.: 44065 Cov.: 31

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.745

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.756

GnomAD2 exomes AF: 0.818 AC: 203928 AN: 249272 AF XY: 0.825

Gnomad AFR exome AF: 0.401

Gnomad AMR exome AF: 0.827

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.780

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.822

GnomAD4 exome AF: 0.861 AC: 1258443 AN: 1461594 Hom.: 547255 Cov.: 52 AF XY: 0.860 AC XY: 625284 AN XY: 727084

African (AFR) AF: 0.387 AC: 12942 AN: 33466

American (AMR) AF: 0.822 AC: 36744 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20435 AN: 26132

East Asian (EAS) AF: 0.773 AC: 30685 AN: 39686

South Asian (SAS) AF: 0.794 AC: 68467 AN: 86236

European-Finnish (FIN) AF: 0.876 AC: 46775 AN: 53408

Middle Eastern (MID) AF: 0.794 AC: 4581 AN: 5766

European-Non Finnish (NFE) AF: 0.889 AC: 987863 AN: 1111802

Other (OTH) AF: 0.827 AC: 49951 AN: 60380

GnomAD4 genome AF: 0.735 AC: 111674 AN: 151990 Hom.: 44065 Cov.: 31 AF XY: 0.736 AC XY: 54668 AN XY: 74290

African (AFR) AF: 0.419 AC: 17318 AN: 41370

American (AMR) AF: 0.790 AC: 12056 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2754 AN: 3468

East Asian (EAS) AF: 0.789 AC: 4083 AN: 5176

South Asian (SAS) AF: 0.782 AC: 3764 AN: 4814

European-Finnish (FIN) AF: 0.865 AC: 9144 AN: 10574

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.881 AC: 59941 AN: 68008

Other (OTH) AF: 0.754 AC: 1590 AN: 2108

Alfa AF: 0.819 Hom.: 153958

Bravo AF: 0.715

Asia WGS AF: 0.753 AC: 2620 AN: 3478

EpiCase AF: 0.877

EpiControl AF: 0.871

ClinVar

ClinVar submissions

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.0
DANN	Benign	0.72
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.37
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.036
Sift	Benign	0.19	T
Sift4G	Benign	0.27	T
Varity_R		0.026
gMVP		0.16
Mutation Taster		=296/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4027402;

hg19: chr14-64496749;

COSMIC: COSV107422304;