rs2747662

Variant names:

• chr6-152145539-T-C
• rs2747662
• NM_001347702.2:c.1458A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_033071.5(SYNE1):​c.24780A>G​(p.Glu8260Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,612,136 control chromosomes in the GnomAD database, including 89,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8863 hom., cov: 31)
  • Exomes 𝑓: 0.33 (80854 hom.)
• Consequence: SYNE1 NM_033071.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.569
• Publications: 21 publications found

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

SYNE1 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300811 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 6-152145539-T-C is Benign according to our data. Variant chr6-152145539-T-C is described in ClinVar as Benign. ClinVar VariationId is 130429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.569 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033071.5. 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
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.1458A>G	p.Glu486Glu	synonymous	Exon 9 of 18	NP_001334631.1
	SYNE1	NM_182961.4	MANE Select	c.24977-1774A>G		intron	N/A	NP_892006.3
	SYNE1	NM_033071.5		c.24780A>G	p.Glu8260Glu	synonymous	Exon 137 of 146	NP_149062.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.1458A>G	p.Glu486Glu	synonymous	Exon 9 of 18	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.24780A>G	p.Glu8260Glu	synonymous	Exon 137 of 146	ENSP00000396024.1
	SYNE1	ENST00000367251.7	TSL:1	c.3759A>G	p.Glu1253Glu	synonymous	Exon 23 of 31	ENSP00000356220.3

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51144 AN: 151794 Hom.: 8857 Cov.: 31

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.386

GnomAD2 exomes AF: 0.352 AC: 88527 AN: 251410 AF XY: 0.350

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.301

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.320

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.329 AC: 480152 AN: 1460224 Hom.: 80854 Cov.: 34 AF XY: 0.331 AC XY: 240302 AN XY: 726490

African (AFR) AF: 0.329 AC: 10994 AN: 33454

American (AMR) AF: 0.498 AC: 22276 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 10474 AN: 26114

East Asian (EAS) AF: 0.309 AC: 12279 AN: 39688

South Asian (SAS) AF: 0.407 AC: 35064 AN: 86218

European-Finnish (FIN) AF: 0.220 AC: 11771 AN: 53402

Middle Eastern (MID) AF: 0.401 AC: 2309 AN: 5758

European-Non Finnish (NFE) AF: 0.319 AC: 354539 AN: 1110542

Other (OTH) AF: 0.339 AC: 20446 AN: 60330

GnomAD4 genome AF: 0.337 AC: 51185 AN: 151912 Hom.: 8863 Cov.: 31 AF XY: 0.338 AC XY: 25068 AN XY: 74244

African (AFR) AF: 0.335 AC: 13891 AN: 41414

American (AMR) AF: 0.458 AC: 6991 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1392 AN: 3468

East Asian (EAS) AF: 0.310 AC: 1589 AN: 5134

South Asian (SAS) AF: 0.401 AC: 1924 AN: 4804

European-Finnish (FIN) AF: 0.215 AC: 2279 AN: 10584

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21926 AN: 67938

Other (OTH) AF: 0.384 AC: 808 AN: 2102

Alfa AF: 0.345 Hom.: 14469

Bravo AF: 0.357

Asia WGS AF: 0.345 AC: 1198 AN: 3476

EpiCase AF: 0.330

EpiControl AF: 0.335

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.61
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2747662; hg19: chr6-152466674; COSMIC: COSV54911291; COSMIC: COSV54911291;