rs4343926

Variant names:

• chr6-152472440-A-G
• rs4343926
• NM_182961.4:c.1351-27T>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.1351-27T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,561,490 control chromosomes in the GnomAD database, including 135,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22009 hom., cov: 30)
  • Exomes 𝑓: 0.41 (113053 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.751
• 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: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 6-152472440-A-G is Benign according to our data. Variant chr6-152472440-A-G is described in ClinVar as Benign. ClinVar VariationId is 262163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.1351-27T>C		intron_variant	Intron 14 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.1351-27T>C		intron_variant	Intron 14 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78306 AN: 151308 Hom.: 21970 Cov.: 30

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.521

GnomAD2 exomes AF: 0.441 AC: 104142 AN: 236384 AF XY: 0.442

Gnomad AFR exome AF: 0.726

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.720

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.413 AC: 581712 AN: 1410066 Hom.: 113053 Cov.: 26 AF XY: 0.416 AC XY: 292291 AN XY: 703332

African (AFR) AF: 0.715 AC: 22766 AN: 31834

American (AMR) AF: 0.320 AC: 14011 AN: 43736

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 11794 AN: 25462

East Asian (EAS) AF: 0.714 AC: 26728 AN: 37412

South Asian (SAS) AF: 0.490 AC: 40708 AN: 83064

European-Finnish (FIN) AF: 0.381 AC: 20042 AN: 52606

Middle Eastern (MID) AF: 0.493 AC: 2765 AN: 5604

European-Non Finnish (NFE) AF: 0.389 AC: 417105 AN: 1072142

Other (OTH) AF: 0.443 AC: 25793 AN: 58206

GnomAD4 genome AF: 0.518 AC: 78395 AN: 151424 Hom.: 22009 Cov.: 30 AF XY: 0.516 AC XY: 38183 AN XY: 73962

African (AFR) AF: 0.731 AC: 30160 AN: 41284

American (AMR) AF: 0.417 AC: 6348 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1709 AN: 3458

East Asian (EAS) AF: 0.755 AC: 3852 AN: 5102

South Asian (SAS) AF: 0.538 AC: 2582 AN: 4796

European-Finnish (FIN) AF: 0.383 AC: 4009 AN: 10478

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28245 AN: 67798

Other (OTH) AF: 0.520 AC: 1090 AN: 2096

Alfa AF: 0.445 Hom.: 14025

Bravo AF: 0.531

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

Aug 13, 2019

GeneDx

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	-0.70
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		0.75
PromoterAI		0.025	Neutral
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: rs4343926; hg19: chr6-152793575; COSMIC: COSV55022987; COSMIC: COSV55022987;