6-152499260-G-C

Variant names:

• chr6-152499260-G-C
• rs2623963
• NM_182961.4:c.889-468C>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.889-468C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 151,800 control chromosomes in the GnomAD database, including 3,142 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 0.20 (3142 hom., cov: 32)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0940
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.889-468C>G		intron_variant	Intron 10 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.889-468C>G		intron_variant	Intron 10 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.198 AC: 29978 AN: 151682 Hom.: 3143 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.219

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

GnomAD4 genome AF: 0.198 AC: 29998 AN: 151800 Hom.: 3142 Cov.: 32 AF XY: 0.197 AC XY: 14613 AN XY: 74162

African (AFR) AF: 0.142 AC: 5898 AN: 41424

American (AMR) AF: 0.206 AC: 3142 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 772 AN: 3472

East Asian (EAS) AF: 0.295 AC: 1519 AN: 5154

South Asian (SAS) AF: 0.280 AC: 1349 AN: 4822

European-Finnish (FIN) AF: 0.185 AC: 1944 AN: 10528

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14726 AN: 67826

Other (OTH) AF: 0.221 AC: 464 AN: 2104

Alfa AF: 0.128 Hom.: 222

Bravo AF: 0.196

Asia WGS AF: 0.275 AC: 955 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.55
PhyloP100		-0.094
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: rs2623963; hg19: chr6-152820395;