6-152145447-A-G

Variant names:

• chr6-152145447-A-G
• rs2813487
• NM_182961.4:c.24977-1682T>C

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.24977-1682T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,581,206 control chromosomes in the GnomAD database, including 93,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10949 hom., cov: 31)
  • Exomes 𝑓: 0.33 (82081 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.983
• 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

ENSG00000300811 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-152145447-A-G is Benign according to our data. Variant chr6-152145447-A-G is described in ClinVar as [Benign]. Clinvar id is 262190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.24977-1682T>C		intron_variant	Intron 137 of 145	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.1510+40T>C		intron_variant	Intron 9 of 17	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.24977-1682T>C		intron_variant	Intron 137 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.1510+40T>C		intron_variant	Intron 9 of 17	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56427 AN: 151762 Hom.: 10936 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.413

GnomAD2 exomes AF: 0.364 AC: 90823 AN: 249238 AF XY: 0.360

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.302

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.334 AC: 477986 AN: 1429328 Hom.: 82081 Cov.: 25 AF XY: 0.336 AC XY: 239834 AN XY: 713170

African (AFR) AF: 0.442 AC: 14486 AN: 32800

American (AMR) AF: 0.507 AC: 22522 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 10553 AN: 25888

East Asian (EAS) AF: 0.310 AC: 12226 AN: 39494

South Asian (SAS) AF: 0.415 AC: 35429 AN: 85472

European-Finnish (FIN) AF: 0.225 AC: 11970 AN: 53296

Middle Eastern (MID) AF: 0.410 AC: 2177 AN: 5308

European-Non Finnish (NFE) AF: 0.321 AC: 347918 AN: 1083382

Other (OTH) AF: 0.350 AC: 20705 AN: 59232

GnomAD4 genome AF: 0.372 AC: 56486 AN: 151878 Hom.: 10949 Cov.: 31 AF XY: 0.372 AC XY: 27617 AN XY: 74248

African (AFR) AF: 0.447 AC: 18528 AN: 41422

American (AMR) AF: 0.470 AC: 7178 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1416 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1604 AN: 5144

South Asian (SAS) AF: 0.408 AC: 1955 AN: 4794

European-Finnish (FIN) AF: 0.222 AC: 2343 AN: 10546

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22200 AN: 67928

Other (OTH) AF: 0.415 AC: 873 AN: 2106

Alfa AF: 0.345 Hom.: 22058

Bravo AF: 0.395

Asia WGS AF: 0.375 AC: 1302 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	-0.85
CADD	Benign	5.5
DANN	Benign	0.64
PhyloP100		0.98
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: rs2813487; hg19: chr6-152466582; COSMIC: COSV54911281; COSMIC: COSV54911281;