rs2747665

Variant names:

• chr6-152147308-T-C
• rs2747665
• NM_182961.4:c.24976+737A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182961.4(SYNE1):​c.24976+737A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 152,074 control chromosomes in the GnomAD database, including 11,037 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (11032 hom., cov: 32)
  • Exomes 𝑓: 0.31 (5 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.511
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.24976+737A>G		intron_variant	Intron 137 of 145	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.1441+737A>G		intron_variant	Intron 8 of 17	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.24976+737A>G		intron_variant	Intron 137 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.1441+737A>G		intron_variant	Intron 8 of 17	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56601 AN: 151882 Hom.: 11018 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.413

GnomAD4 exome AF: 0.311 AC: 23 AN: 74 Hom.: 5 Cov.: 0 AF XY: 0.290 AC XY: 18 AN XY: 62

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.306 AC: 19 AN: 62

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.373 AC: 56661 AN: 152000 Hom.: 11032 Cov.: 32 AF XY: 0.373 AC XY: 27681 AN XY: 74302

African (AFR) AF: 0.451 AC: 18661 AN: 41422

American (AMR) AF: 0.472 AC: 7212 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1487 AN: 3470

East Asian (EAS) AF: 0.310 AC: 1593 AN: 5140

South Asian (SAS) AF: 0.407 AC: 1960 AN: 4818

European-Finnish (FIN) AF: 0.217 AC: 2297 AN: 10582

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22194 AN: 67966

Other (OTH) AF: 0.411 AC: 868 AN: 2112

Alfa AF: 0.368 Hom.: 1678

Bravo AF: 0.397

Asia WGS AF: 0.353 AC: 1227 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.42
PhyloP100		-0.51
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: rs2747665; hg19: chr6-152468443; COSMIC: COSV54938458; COSMIC: COSV54938458;