rs115809466

Variant names:

• chr14-64049885-A-G
• rs115809466
• NM_182914.3:c.7643+9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):​c.7643+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,578 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (10 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.353
• Publications: 1 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=-0.88).
• BP6: Variant 14-64049885-A-G is Benign according to our data. Variant chr14-64049885-A-G is described in ClinVar as Benign. ClinVar VariationId is 313533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00547 (834/152344) while in subpopulation AFR AF = 0.0191 (795/41580). AF 95% confidence interval is 0.018. There are 8 homozygotes in GnomAd4. There are 381 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 834 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.7643+9A>G		intron	N/A	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.7643+9A>G		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.7643+9A>G		intron	N/A	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.7643+9A>G		intron	N/A	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.7643+9A>G		intron	N/A	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 828 AN: 152226 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00137 AC: 341 AN: 248638 AF XY: 0.00114

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.000930

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000541 AC: 791 AN: 1461234 Hom.: 10 Cov.: 31 AF XY: 0.000457 AC XY: 332 AN XY: 726812

African (AFR) AF: 0.0195 AC: 652 AN: 33478

American (AMR) AF: 0.000962 AC: 43 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111574

Other (OTH) AF: 0.00124 AC: 75 AN: 60368

GnomAD4 genome AF: 0.00547 AC: 834 AN: 152344 Hom.: 8 Cov.: 32 AF XY: 0.00511 AC XY: 381 AN XY: 74504

African (AFR) AF: 0.0191 AC: 795 AN: 41580

American (AMR) AF: 0.00176 AC: 27 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00278 Hom.: 3

Bravo AF: 0.00625

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.64
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

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: rs115809466; hg19: chr14-64516603;