rs116292261

Variant names:

• chr6-152206120-C-T
• rs116292261
• NM_182961.4:c.23019+48G>A

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.23019+48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,571,386 control chromosomes in the GnomAD database, including 1,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (582 hom., cov: 33)
  • Exomes 𝑓: 0.012 (864 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.189
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-152206120-C-T is Benign according to our data. Variant chr6-152206120-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.23019+48G>A		intron_variant	Intron 126 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.23019+48G>A		intron_variant	Intron 126 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.0522 AC: 7942 AN: 152180 Hom.: 580 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0515

Gnomad SAS AF: 0.0801

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0269 AC: 6364 AN: 236986 AF XY: 0.0267

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.0460

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0123 AC: 17396 AN: 1419088 Hom.: 864 Cov.: 28 AF XY: 0.0135 AC XY: 9552 AN XY: 707482

African (AFR) AF: 0.163 AC: 5314 AN: 32656

American (AMR) AF: 0.0108 AC: 471 AN: 43664

Ashkenazi Jewish (ASJ) AF: 0.00194 AC: 50 AN: 25716

East Asian (EAS) AF: 0.0727 AC: 2861 AN: 39364

South Asian (SAS) AF: 0.0663 AC: 5592 AN: 84296

European-Finnish (FIN) AF: 0.0151 AC: 790 AN: 52400

Middle Eastern (MID) AF: 0.0242 AC: 103 AN: 4248

European-Non Finnish (NFE) AF: 0.000923 AC: 995 AN: 1077970

Other (OTH) AF: 0.0208 AC: 1220 AN: 58774

GnomAD4 genome AF: 0.0523 AC: 7967 AN: 152298 Hom.: 582 Cov.: 33 AF XY: 0.0540 AC XY: 4019 AN XY: 74482

African (AFR) AF: 0.159 AC: 6603 AN: 41536

American (AMR) AF: 0.0216 AC: 331 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.0518 AC: 269 AN: 5190

South Asian (SAS) AF: 0.0796 AC: 384 AN: 4826

European-Finnish (FIN) AF: 0.0147 AC: 156 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00181 AC: 123 AN: 68022

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0269 Hom.: 162

Bravo AF: 0.0558

Asia WGS AF: 0.0650 AC: 225 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	0.29
DANN	Benign	0.71
PhyloP100		-0.19
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: rs116292261; hg19: chr6-152527255;