chr6-152526200-G-A

Variant names:

• chr6-152526200-G-A
• rs2141152
• NM_182961.4:c.130-25C>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.130-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,600,598 control chromosomes in the GnomAD database, including 84,116 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 0.27 (6476 hom., cov: 32)
  • Exomes 𝑓: 0.32 (77640 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.334
• 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=-0.77).
• BP6: Variant 6-152526200-G-A is Benign according to our data. Variant chr6-152526200-G-A is described in ClinVar as Benign. ClinVar VariationId is 262161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.130-25C>T		intron_variant	Intron 4 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.130-25C>T		intron_variant	Intron 4 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41182 AN: 151956 Hom.: 6477 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.294 AC: 73453 AN: 249680 AF XY: 0.300

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.322 AC: 465901 AN: 1448524 Hom.: 77640 Cov.: 28 AF XY: 0.320 AC XY: 230913 AN XY: 721388

African (AFR) AF: 0.127 AC: 4224 AN: 33218

American (AMR) AF: 0.147 AC: 6571 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 7210 AN: 26024

East Asian (EAS) AF: 0.463 AC: 18324 AN: 39594

South Asian (SAS) AF: 0.245 AC: 21053 AN: 85916

European-Finnish (FIN) AF: 0.458 AC: 24342 AN: 53154

Middle Eastern (MID) AF: 0.241 AC: 1382 AN: 5742

European-Non Finnish (NFE) AF: 0.331 AC: 364408 AN: 1100334

Other (OTH) AF: 0.307 AC: 18387 AN: 59906

GnomAD4 genome AF: 0.271 AC: 41189 AN: 152074 Hom.: 6476 Cov.: 32 AF XY: 0.278 AC XY: 20620 AN XY: 74306

African (AFR) AF: 0.132 AC: 5483 AN: 41494

American (AMR) AF: 0.201 AC: 3066 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 982 AN: 3468

East Asian (EAS) AF: 0.454 AC: 2340 AN: 5158

South Asian (SAS) AF: 0.254 AC: 1224 AN: 4824

European-Finnish (FIN) AF: 0.473 AC: 4993 AN: 10554

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22164 AN: 67990

Other (OTH) AF: 0.249 AC: 525 AN: 2108

Alfa AF: 0.306 Hom.: 5599

Bravo AF: 0.246

Asia WGS AF: 0.322 AC: 1119 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 26, 2018

GeneDx

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.77
DANN	Benign	0.71
PhyloP100		-0.33
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: rs2141152; hg19: chr6-152847335; COSMIC: COSV54993301;