rs2253512

Variant names:

• chr6-152201791-G-A
• rs2253512
• NM_182961.4:c.23145+33C>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.23145+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,416 control chromosomes in the GnomAD database, including 20,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1588 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19270 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.292
• Publications: 7 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 6-152201791-G-A is Benign according to our data. Variant chr6-152201791-G-A is described in ClinVar as Benign. ClinVar VariationId is 262185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.23145+33C>T		intron_variant	Intron 127 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.23145+33C>T		intron_variant	Intron 127 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20493 AN: 152028 Hom.: 1591 Cov.: 32

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.149 AC: 37451 AN: 250708 AF XY: 0.152

Gnomad AFR exome AF: 0.0634

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.160 AC: 233282 AN: 1461270 Hom.: 19270 Cov.: 33 AF XY: 0.160 AC XY: 116334 AN XY: 726968

African (AFR) AF: 0.0643 AC: 2150 AN: 33462

American (AMR) AF: 0.132 AC: 5914 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4535 AN: 26122

East Asian (EAS) AF: 0.129 AC: 5121 AN: 39692

South Asian (SAS) AF: 0.139 AC: 11959 AN: 86242

European-Finnish (FIN) AF: 0.139 AC: 7441 AN: 53412

Middle Eastern (MID) AF: 0.204 AC: 1173 AN: 5758

European-Non Finnish (NFE) AF: 0.167 AC: 185259 AN: 1111510

Other (OTH) AF: 0.161 AC: 9730 AN: 60366

GnomAD4 genome AF: 0.135 AC: 20495 AN: 152146 Hom.: 1588 Cov.: 32 AF XY: 0.133 AC XY: 9914 AN XY: 74368

African (AFR) AF: 0.0643 AC: 2670 AN: 41530

American (AMR) AF: 0.161 AC: 2457 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 584 AN: 3468

East Asian (EAS) AF: 0.128 AC: 662 AN: 5168

South Asian (SAS) AF: 0.141 AC: 682 AN: 4826

European-Finnish (FIN) AF: 0.126 AC: 1337 AN: 10578

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11559 AN: 67974

Other (OTH) AF: 0.169 AC: 355 AN: 2106

Alfa AF: 0.155 Hom.: 853

Bravo AF: 0.133

Asia WGS AF: 0.142 AC: 495 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	3.8
DANN	Benign	0.72
PhyloP100		0.29
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: rs2253512; hg19: chr6-152522926; COSMIC: COSV55114184;