rs9479298

Variant names:

• chr6-152337056-T-C
• rs9479298
• NM_182961.4:c.12352-39A>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.12352-39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 1,592,616 control chromosomes in the GnomAD database, including 453,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48655 hom., cov: 32)
  • Exomes 𝑓: 0.75 (405079 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.10
• Publications: 7 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=-0.87).
• BP6: Variant 6-152337056-T-C is Benign according to our data. Variant chr6-152337056-T-C is described in ClinVar as Benign. ClinVar VariationId is 262158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.12352-39A>G		intron_variant	Intron 75 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.12352-39A>G		intron_variant	Intron 75 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.12139-39A>G		intron_variant	Intron 74 of 145	1		ENSP00000396024.1
SYNE1	ENST00000471834.1	n.5490-39A>G		intron_variant	Intron 18 of 18	1

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120914 AN: 152068 Hom.: 48590 Cov.: 32

Gnomad AFR AF: 0.919

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.752

GnomAD2 exomes AF: 0.748 AC: 168702 AN: 225452 AF XY: 0.740

Gnomad AFR exome AF: 0.923

Gnomad AMR exome AF: 0.698

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.856

Gnomad FIN exome AF: 0.834

Gnomad NFE exome AF: 0.747

Gnomad OTH exome AF: 0.742

GnomAD4 exome AF: 0.748 AC: 1077440 AN: 1440430 Hom.: 405079 Cov.: 31 AF XY: 0.744 AC XY: 532077 AN XY: 715622

African (AFR) AF: 0.922 AC: 30676 AN: 33284

American (AMR) AF: 0.703 AC: 29810 AN: 42400

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 18092 AN: 25818

East Asian (EAS) AF: 0.860 AC: 33939 AN: 39456

South Asian (SAS) AF: 0.623 AC: 52750 AN: 84670

European-Finnish (FIN) AF: 0.828 AC: 39713 AN: 47968

Middle Eastern (MID) AF: 0.616 AC: 3503 AN: 5686

European-Non Finnish (NFE) AF: 0.748 AC: 824424 AN: 1101440

Other (OTH) AF: 0.746 AC: 44533 AN: 59708

GnomAD4 genome AF: 0.795 AC: 121041 AN: 152186 Hom.: 48655 Cov.: 32 AF XY: 0.796 AC XY: 59203 AN XY: 74402

African (AFR) AF: 0.919 AC: 38165 AN: 41528

American (AMR) AF: 0.724 AC: 11071 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2379 AN: 3466

East Asian (EAS) AF: 0.848 AC: 4389 AN: 5174

South Asian (SAS) AF: 0.625 AC: 3020 AN: 4834

European-Finnish (FIN) AF: 0.832 AC: 8808 AN: 10588

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.747 AC: 50787 AN: 68000

Other (OTH) AF: 0.756 AC: 1590 AN: 2104

Alfa AF: 0.779 Hom.: 9724

Bravo AF: 0.795

Asia WGS AF: 0.771 AC: 2684 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0010
DANN	Benign	0.40
PhyloP100		-5.1
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: rs9479298; hg19: chr6-152658191;