rs214968

Variant names:

• chr6-152455615-G-A
• rs214968
• NM_182961.4:c.2728-25C>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.2728-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,611,340 control chromosomes in the GnomAD database, including 48,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5955 hom., cov: 33)
  • Exomes 𝑓: 0.24 (42397 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0830
• Publications: 9 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=-0.81).
• BP6: Variant 6-152455615-G-A is Benign according to our data. Variant chr6-152455615-G-A is described in ClinVar as Benign. ClinVar VariationId is 262195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.2728-25C>T		intron_variant	Intron 23 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.2728-25C>T		intron_variant	Intron 23 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41189 AN: 151982 Hom.: 5948 Cov.: 33

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.274

GnomAD2 exomes AF: 0.251 AC: 63081 AN: 251076 AF XY: 0.252

Gnomad AFR exome AF: 0.371

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.335

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.236 AC: 344897 AN: 1459242 Hom.: 42397 Cov.: 31 AF XY: 0.238 AC XY: 172975 AN XY: 726124

African (AFR) AF: 0.366 AC: 12249 AN: 33422

American (AMR) AF: 0.218 AC: 9752 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5988 AN: 26120

East Asian (EAS) AF: 0.351 AC: 13920 AN: 39684

South Asian (SAS) AF: 0.286 AC: 24608 AN: 86186

European-Finnish (FIN) AF: 0.185 AC: 9861 AN: 53380

Middle Eastern (MID) AF: 0.309 AC: 1782 AN: 5762

European-Non Finnish (NFE) AF: 0.227 AC: 251768 AN: 1109660

Other (OTH) AF: 0.248 AC: 14969 AN: 60312

GnomAD4 genome AF: 0.271 AC: 41232 AN: 152098 Hom.: 5955 Cov.: 33 AF XY: 0.268 AC XY: 19887 AN XY: 74342

African (AFR) AF: 0.364 AC: 15114 AN: 41476

American (AMR) AF: 0.240 AC: 3670 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 805 AN: 3468

East Asian (EAS) AF: 0.327 AC: 1694 AN: 5180

South Asian (SAS) AF: 0.288 AC: 1386 AN: 4812

European-Finnish (FIN) AF: 0.181 AC: 1908 AN: 10570

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.234 AC: 15882 AN: 67998

Other (OTH) AF: 0.275 AC: 582 AN: 2114

Alfa AF: 0.260 Hom.: 2739

Bravo AF: 0.281

Asia WGS AF: 0.292 AC: 1018 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.31
DANN	Benign	0.26
PhyloP100		-0.083
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: rs214968; hg19: chr6-152776750; COSMIC: COSV54990723; COSMIC: COSV54990723;