6-152136939-G-A

Variant names:

• chr6-152136939-G-A
• rs2813566
• NM_182961.4:c.25459-121C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182961.4(SYNE1):​c.25459-121C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,065,856 control chromosomes in the GnomAD database, including 47,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (7550 hom., cov: 32)
  • Exomes 𝑓: 0.29 (39970 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.163
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-152136939-G-A is Benign according to our data. Variant chr6-152136939-G-A is described in ClinVar as Benign. ClinVar VariationId is 670219.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.25459-121C>T		intron_variant	Intron 140 of 145	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.1993-121C>T		intron_variant	Intron 12 of 17	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.25459-121C>T		intron_variant	Intron 140 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.1993-121C>T		intron_variant	Intron 12 of 17	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47148 AN: 151970 Hom.: 7554 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.342

GnomAD4 exome AF: 0.287 AC: 262131 AN: 913768 Hom.: 39970 AF XY: 0.291 AC XY: 137085 AN XY: 471144

African (AFR) AF: 0.343 AC: 7747 AN: 22560

American (AMR) AF: 0.450 AC: 16105 AN: 35772

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 7700 AN: 22252

East Asian (EAS) AF: 0.319 AC: 11017 AN: 34510

South Asian (SAS) AF: 0.391 AC: 27250 AN: 69756

European-Finnish (FIN) AF: 0.175 AC: 6516 AN: 37264

Middle Eastern (MID) AF: 0.346 AC: 1418 AN: 4102

European-Non Finnish (NFE) AF: 0.266 AC: 171721 AN: 645072

Other (OTH) AF: 0.298 AC: 12657 AN: 42480

GnomAD4 genome AF: 0.310 AC: 47182 AN: 152088 Hom.: 7550 Cov.: 32 AF XY: 0.311 AC XY: 23137 AN XY: 74360

African (AFR) AF: 0.351 AC: 14540 AN: 41466

American (AMR) AF: 0.408 AC: 6240 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1206 AN: 3470

East Asian (EAS) AF: 0.325 AC: 1683 AN: 5172

South Asian (SAS) AF: 0.388 AC: 1865 AN: 4810

European-Finnish (FIN) AF: 0.171 AC: 1809 AN: 10578

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18778 AN: 67992

Other (OTH) AF: 0.342 AC: 720 AN: 2108

Alfa AF: 0.293 Hom.: 3516

Bravo AF: 0.331

Asia WGS AF: 0.339 AC: 1175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.73
DANN	Benign	0.60
PhyloP100		-0.16
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: rs2813566; hg19: chr6-152458074; COSMIC: COSV55082848;