rs2252837

Variant names:

• chr6-152147685-C-T
• rs2252837
• NM_182961.4:c.24976+360G>A

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+360G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 288,244 control chromosomes in the GnomAD database, including 16,481 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 0.36 (10304 hom., cov: 32)
  • Exomes 𝑓: 0.29 (6177 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.136
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.24976+360G>A		intron_variant	Intron 137 of 145	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.1441+360G>A		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+360G>A		intron_variant	Intron 137 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.1441+360G>A		intron_variant	Intron 8 of 17	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54921 AN: 151764 Hom.: 10290 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.403

GnomAD4 exome AF: 0.292 AC: 39755 AN: 136362 Hom.: 6177 Cov.: 0 AF XY: 0.300 AC XY: 22214 AN XY: 74032

African (AFR) AF: 0.338 AC: 1025 AN: 3034

American (AMR) AF: 0.427 AC: 2098 AN: 4916

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1141 AN: 3146

East Asian (EAS) AF: 0.236 AC: 1126 AN: 4776

South Asian (SAS) AF: 0.341 AC: 8194 AN: 24044

European-Finnish (FIN) AF: 0.186 AC: 1280 AN: 6868

Middle Eastern (MID) AF: 0.380 AC: 190 AN: 500

European-Non Finnish (NFE) AF: 0.276 AC: 22632 AN: 82122

Other (OTH) AF: 0.297 AC: 2069 AN: 6956

GnomAD4 genome AF: 0.362 AC: 54983 AN: 151882 Hom.: 10304 Cov.: 32 AF XY: 0.363 AC XY: 26913 AN XY: 74208

African (AFR) AF: 0.416 AC: 17202 AN: 41392

American (AMR) AF: 0.467 AC: 7127 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1432 AN: 3470

East Asian (EAS) AF: 0.306 AC: 1566 AN: 5124

South Asian (SAS) AF: 0.404 AC: 1940 AN: 4806

European-Finnish (FIN) AF: 0.218 AC: 2298 AN: 10562

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22183 AN: 67950

Other (OTH) AF: 0.401 AC: 845 AN: 2106

Alfa AF: 0.345 Hom.: 1153

Bravo AF: 0.384

Asia WGS AF: 0.338 AC: 1175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.70
DANN	Benign	0.47
PhyloP100		-0.14
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: rs2252837; hg19: chr6-152468820; COSMIC: COSV54938469; COSMIC: COSV54938469;