NM_182961.4:c.68-4400T>C

Variant names:

• chr6-152544421-A-G
• rs1358317
• NM_182961.4:c.68-4400T>C

Variant summary

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

The NM_182961.4(SYNE1):​c.68-4400T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 151,992 control chromosomes in the GnomAD database, including 5,061 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 0.25 (5061 hom., cov: 32)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.700
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.68-4400T>C		intron	N/A	NP_892006.3
	SYNE1	NM_033071.5		c.68-4400T>C		intron	N/A	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.68-4400T>C		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.68-4400T>C		intron	N/A	ENSP00000396024.1
	SYNE1	ENST00000466159.6	TSL:1	c.68-4400T>C		intron	N/A	ENSP00000446021.1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38083 AN: 151874 Hom.: 5055 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.251 AC: 38126 AN: 151992 Hom.: 5061 Cov.: 32 AF XY: 0.248 AC XY: 18431 AN XY: 74286

African (AFR) AF: 0.323 AC: 13409 AN: 41452

American (AMR) AF: 0.225 AC: 3439 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3466

East Asian (EAS) AF: 0.294 AC: 1519 AN: 5166

South Asian (SAS) AF: 0.282 AC: 1355 AN: 4810

European-Finnish (FIN) AF: 0.184 AC: 1951 AN: 10578

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14946 AN: 67946

Other (OTH) AF: 0.254 AC: 535 AN: 2108

Alfa AF: 0.239 Hom.: 1917

Bravo AF: 0.258

Asia WGS AF: 0.289 AC: 1004 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.62
DANN	Benign	0.31
PhyloP100		-0.70
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: rs1358317; hg19: chr6-152865556;