6-152249280-G-A

Variant names:

• chr6-152249280-G-A
• rs6557210
• NM_182961.4:c.19471-18C>T

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.19471-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 1,470,016 control chromosomes in the GnomAD database, including 301,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32283 hom., cov: 32)
  • Exomes 𝑓: 0.64 (269096 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.90
• Publications: 16 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=-0.9).
• BP6: Variant 6-152249280-G-A is Benign according to our data. Variant chr6-152249280-G-A is described in ClinVar as Benign. ClinVar VariationId is 262176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 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.19471-18C>T		intron	N/A	NP_892006.3
	SYNE1	NM_033071.5		c.19258-18C>T		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.19471-18C>T		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.19258-18C>T		intron	N/A	ENSP00000396024.1
	SYNE1	ENST00000367256.9	TSL:1	n.3163-18C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98262 AN: 151940 Hom.: 32247 Cov.: 32

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.596

GnomAD2 exomes AF: 0.658 AC: 165266 AN: 250984 AF XY: 0.655

Gnomad AFR exome AF: 0.655

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.895

Gnomad FIN exome AF: 0.780

Gnomad NFE exome AF: 0.613

Gnomad OTH exome AF: 0.642

GnomAD4 exome AF: 0.637 AC: 839004 AN: 1317958 Hom.: 269096 Cov.: 20 AF XY: 0.635 AC XY: 421899 AN XY: 664054

African (AFR) AF: 0.654 AC: 19981 AN: 30570

American (AMR) AF: 0.623 AC: 27763 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 15319 AN: 25226

East Asian (EAS) AF: 0.878 AC: 34355 AN: 39114

South Asian (SAS) AF: 0.661 AC: 55059 AN: 83280

European-Finnish (FIN) AF: 0.782 AC: 41650 AN: 53270

Middle Eastern (MID) AF: 0.497 AC: 2709 AN: 5456

European-Non Finnish (NFE) AF: 0.618 AC: 606364 AN: 980778

Other (OTH) AF: 0.643 AC: 35804 AN: 55702

GnomAD4 genome AF: 0.647 AC: 98349 AN: 152058 Hom.: 32283 Cov.: 32 AF XY: 0.654 AC XY: 48651 AN XY: 74350

African (AFR) AF: 0.652 AC: 27005 AN: 41450

American (AMR) AF: 0.611 AC: 9332 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2141 AN: 3470

East Asian (EAS) AF: 0.882 AC: 4571 AN: 5184

South Asian (SAS) AF: 0.664 AC: 3200 AN: 4822

European-Finnish (FIN) AF: 0.786 AC: 8322 AN: 10584

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.615 AC: 41799 AN: 67954

Other (OTH) AF: 0.601 AC: 1272 AN: 2116

Alfa AF: 0.614 Hom.: 46138

Bravo AF: 0.635

Asia WGS AF: 0.769 AC: 2673 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 25, 2016

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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.90
CADD	Benign	6.0
DANN	Benign	0.57
PhyloP100		1.9
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: rs6557210; hg19: chr6-152570415; COSMIC: COSV54939047;