chr6-152484789-T-C

Variant names:

• chr6-152484789-T-C
• rs58766460
• NM_182961.4:c.1185+46A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.1185+46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,602,014 control chromosomes in the GnomAD database, including 1,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (767 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (719 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.207
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-152484789-T-C is Benign according to our data. Variant chr6-152484789-T-C is described in ClinVar as Benign. ClinVar VariationId is 262156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 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.1185+46A>G		intron	N/A	NP_892006.3
	SYNE1	NM_033071.5		c.1206+46A>G		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.1185+46A>G		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.1206+46A>G		intron	N/A	ENSP00000396024.1
	SYNE1	ENST00000466159.6	TSL:1	c.1185+46A>G		intron	N/A	ENSP00000446021.1

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8251 AN: 152172 Hom.: 768 Cov.: 33

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0144 AC: 3585 AN: 248486 AF XY: 0.0106

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.00823

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000525

Gnomad OTH exome AF: 0.00676

GnomAD4 exome AF: 0.00561 AC: 8140 AN: 1449724 Hom.: 719 Cov.: 29 AF XY: 0.00481 AC XY: 3475 AN XY: 722050

African (AFR) AF: 0.199 AC: 6594 AN: 33114

American (AMR) AF: 0.0101 AC: 452 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.000466 AC: 40 AN: 85898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52372

Middle Eastern (MID) AF: 0.00821 AC: 47 AN: 5724

European-Non Finnish (NFE) AF: 0.000246 AC: 271 AN: 1102502

Other (OTH) AF: 0.0123 AC: 736 AN: 59924

GnomAD4 genome AF: 0.0543 AC: 8272 AN: 152290 Hom.: 767 Cov.: 33 AF XY: 0.0526 AC XY: 3920 AN XY: 74470

African (AFR) AF: 0.188 AC: 7807 AN: 41522

American (AMR) AF: 0.0225 AC: 345 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68030

Other (OTH) AF: 0.0340 AC: 72 AN: 2116

Alfa AF: 0.0238 Hom.: 136

Bravo AF: 0.0634

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.5
DANN	Benign	0.71
PhyloP100		-0.21
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: rs58766460; hg19: chr6-152805924;