rs7146588

Variant names:

• chr14-64009962-T-A
• rs7146588
• NM_182914.3:c.4578-4T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-64009962-T-A
• chr14-64009962-T-C
• chr14-64009962-T-G

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.4578-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,611,048 control chromosomes in the GnomAD database, including 43,218 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9574 hom., cov: 32)
  • Exomes 𝑓: 0.20 (33644 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.0003185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.335
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-64009962-T-A is Benign according to our data. Variant chr14-64009962-T-A is described in ClinVar as Benign. ClinVar VariationId is 130499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 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.4578-4T>A		splice_region intron	N/A	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.4578-4T>A		splice_region intron	N/A	NP_055995.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.4578-4T>A		splice_region intron	N/A	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.4578-4T>A		splice_region intron	N/A	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.4578-4T>A		splice_region intron	N/A	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47088 AN: 151992 Hom.: 9540 Cov.: 32

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.241 AC: 59843 AN: 248812 AF XY: 0.230

Gnomad AFR exome AF: 0.596

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.221

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.200 AC: 292388 AN: 1458938 Hom.: 33644 Cov.: 31 AF XY: 0.200 AC XY: 144891 AN XY: 725898

African (AFR) AF: 0.609 AC: 20319 AN: 33350

American (AMR) AF: 0.329 AC: 14700 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6619 AN: 26106

East Asian (EAS) AF: 0.270 AC: 10700 AN: 39660

South Asian (SAS) AF: 0.219 AC: 18869 AN: 86138

European-Finnish (FIN) AF: 0.178 AC: 9487 AN: 53396

Middle Eastern (MID) AF: 0.198 AC: 1068 AN: 5394

European-Non Finnish (NFE) AF: 0.178 AC: 197405 AN: 1109964

Other (OTH) AF: 0.219 AC: 13221 AN: 60238

GnomAD4 genome AF: 0.310 AC: 47173 AN: 152110 Hom.: 9574 Cov.: 32 AF XY: 0.309 AC XY: 22953 AN XY: 74356

African (AFR) AF: 0.583 AC: 24161 AN: 41460

American (AMR) AF: 0.303 AC: 4639 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3472

East Asian (EAS) AF: 0.227 AC: 1178 AN: 5184

South Asian (SAS) AF: 0.238 AC: 1150 AN: 4822

European-Finnish (FIN) AF: 0.179 AC: 1890 AN: 10572

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12595 AN: 67990

Other (OTH) AF: 0.280 AC: 591 AN: 2114

Alfa AF: 0.226 Hom.: 1516

Bravo AF: 0.331

Asia WGS AF: 0.265 AC: 919 AN: 3478

EpiCase AF: 0.188

EpiControl AF: 0.188

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)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.0
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: rs7146588; hg19: chr14-64476680; COSMIC: COSV59952600;