6-152401093-A-G

Variant names:

• chr6-152401093-A-G
• rs177330
• NM_182961.4:c.7029+45T>C

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.7029+45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,581,814 control chromosomes in the GnomAD database, including 131,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15834 hom., cov: 32)
  • Exomes 𝑓: 0.39 (115919 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00200
• Publications: 11 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=-0.84).
• BP6: Variant 6-152401093-A-G is Benign according to our data. Variant chr6-152401093-A-G is described in ClinVar as Benign. ClinVar VariationId is 262198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 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.7029+45T>C		intron	N/A	NP_892006.3
	SYNE1	NM_033071.5		c.7050+45T>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.7029+45T>C		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.7050+45T>C		intron	N/A	ENSP00000396024.1
	SYNE1	ENST00000461872.6	TSL:1	n.7247+45T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67323 AN: 151936 Hom.: 15820 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.437

GnomAD2 exomes AF: 0.423 AC: 104729 AN: 247766 AF XY: 0.425

Gnomad AFR exome AF: 0.567

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.767

Gnomad FIN exome AF: 0.393

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.393 AC: 562513 AN: 1429760 Hom.: 115919 Cov.: 25 AF XY: 0.397 AC XY: 282898 AN XY: 713442

African (AFR) AF: 0.564 AC: 18532 AN: 32870

American (AMR) AF: 0.303 AC: 13484 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9419 AN: 25914

East Asian (EAS) AF: 0.776 AC: 30631 AN: 39476

South Asian (SAS) AF: 0.485 AC: 41485 AN: 85604

European-Finnish (FIN) AF: 0.390 AC: 20411 AN: 52314

Middle Eastern (MID) AF: 0.467 AC: 2662 AN: 5696

European-Non Finnish (NFE) AF: 0.370 AC: 401143 AN: 1084104

Other (OTH) AF: 0.418 AC: 24746 AN: 59228

GnomAD4 genome AF: 0.443 AC: 67385 AN: 152054 Hom.: 15834 Cov.: 32 AF XY: 0.446 AC XY: 33128 AN XY: 74310

African (AFR) AF: 0.564 AC: 23381 AN: 41476

American (AMR) AF: 0.354 AC: 5411 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1323 AN: 3472

East Asian (EAS) AF: 0.757 AC: 3904 AN: 5158

South Asian (SAS) AF: 0.504 AC: 2430 AN: 4822

European-Finnish (FIN) AF: 0.382 AC: 4032 AN: 10562

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25573 AN: 67970

Other (OTH) AF: 0.436 AC: 922 AN: 2116

Alfa AF: 0.407 Hom.: 5247

Bravo AF: 0.445

Asia WGS AF: 0.587 AC: 2042 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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.

Arthrogryposis multiplex congenita 3, myogenic type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive ataxia, Beauce type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.50
PhyloP100		0.0020
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: rs177330; hg19: chr6-152722228;