rs6932325

Variant names:

• chr6-152352384-A-C
• rs6932325
• NM_182961.4:c.11254-31T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-152352384-A-C
• chr6-152352384-A-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.11254-31T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,599,144 control chromosomes in the GnomAD database, including 289,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.58 (25233 hom., cov: 30)
  • Exomes 𝑓: 0.60 (264380 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.349
• Publications: 8 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-152352384-A-C is Benign according to our data. Variant chr6-152352384-A-C is described in ClinVar as Benign. ClinVar VariationId is 262153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.11254-31T>G		intron_variant	Intron 69 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.11254-31T>G		intron_variant	Intron 69 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.11209-31T>G		intron_variant	Intron 69 of 145	1		ENSP00000396024.1
SYNE1	ENST00000471834.1	n.4392-31T>G		intron_variant	Intron 12 of 18	1

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87102 AN: 151274 Hom.: 25216 Cov.: 30

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.591

GnomAD2 exomes AF: 0.583 AC: 142089 AN: 243540 AF XY: 0.582

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.603

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.603 AC: 873439 AN: 1447762 Hom.: 264380 Cov.: 30 AF XY: 0.601 AC XY: 432844 AN XY: 720434

African (AFR) AF: 0.499 AC: 16372 AN: 32794

American (AMR) AF: 0.601 AC: 26147 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 16728 AN: 25874

East Asian (EAS) AF: 0.639 AC: 25331 AN: 39626

South Asian (SAS) AF: 0.523 AC: 44057 AN: 84196

European-Finnish (FIN) AF: 0.545 AC: 28840 AN: 52874

Middle Eastern (MID) AF: 0.513 AC: 2927 AN: 5710

European-Non Finnish (NFE) AF: 0.614 AC: 677338 AN: 1103326

Other (OTH) AF: 0.596 AC: 35699 AN: 59868

GnomAD4 genome AF: 0.576 AC: 87161 AN: 151382 Hom.: 25233 Cov.: 30 AF XY: 0.572 AC XY: 42273 AN XY: 73910

African (AFR) AF: 0.512 AC: 21142 AN: 41254

American (AMR) AF: 0.613 AC: 9337 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2222 AN: 3468

East Asian (EAS) AF: 0.619 AC: 3178 AN: 5130

South Asian (SAS) AF: 0.535 AC: 2568 AN: 4798

European-Finnish (FIN) AF: 0.531 AC: 5464 AN: 10294

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41341 AN: 67880

Other (OTH) AF: 0.593 AC: 1249 AN: 2108

Alfa AF: 0.537 Hom.: 3480

Bravo AF: 0.580

Asia WGS AF: 0.594 AC: 2069 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	-0.90
CADD	Benign	0.90
DANN	Benign	0.29
PhyloP100		-0.35
BranchPoint Hunter		0.0
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: rs6932325; hg19: chr6-152673519; COSMIC: COSV55004686;