NM_182961.4:c.1185+81G>A

Variant names:

• chr6-152484754-C-T
• rs9397512
• NM_182961.4:c.1185+81G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182961.4(SYNE1):​c.1185+81G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,474,156 control chromosomes in the GnomAD database, including 154,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (22302 hom., cov: 33)
  • Exomes 𝑓: 0.44 (132476 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.470
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-152484754-C-T is Benign according to our data. Variant chr6-152484754-C-T is described in ClinVar as Benign. ClinVar VariationId is 670600.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.1185+81G>A		intron_variant	Intron 13 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.1185+81G>A		intron_variant	Intron 13 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.520 AC: 79070 AN: 151934 Hom.: 22261 Cov.: 33

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.525

GnomAD4 exome AF: 0.438 AC: 579449 AN: 1322104 Hom.: 132476 AF XY: 0.441 AC XY: 292391 AN XY: 662424

African (AFR) AF: 0.732 AC: 22182 AN: 30316

American (AMR) AF: 0.338 AC: 14452 AN: 42784

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 12082 AN: 25064

East Asian (EAS) AF: 0.780 AC: 29429 AN: 37752

South Asian (SAS) AF: 0.524 AC: 42340 AN: 80840

European-Finnish (FIN) AF: 0.404 AC: 18887 AN: 46746

Middle Eastern (MID) AF: 0.519 AC: 2564 AN: 4944

European-Non Finnish (NFE) AF: 0.412 AC: 411377 AN: 998076

Other (OTH) AF: 0.470 AC: 26136 AN: 55582

GnomAD4 genome AF: 0.521 AC: 79161 AN: 152052 Hom.: 22302 Cov.: 33 AF XY: 0.519 AC XY: 38610 AN XY: 74324

African (AFR) AF: 0.725 AC: 30089 AN: 41502

American (AMR) AF: 0.424 AC: 6471 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1701 AN: 3472

East Asian (EAS) AF: 0.758 AC: 3917 AN: 5166

South Asian (SAS) AF: 0.542 AC: 2617 AN: 4826

European-Finnish (FIN) AF: 0.399 AC: 4214 AN: 10554

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28642 AN: 67944

Other (OTH) AF: 0.524 AC: 1103 AN: 2106

Alfa AF: 0.468 Hom.: 3001

Bravo AF: 0.530

Asia WGS AF: 0.631 AC: 2196 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.88
CADD	Benign	0.28
DANN	Benign	0.40
PhyloP100		-0.47
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: rs9397512; hg19: chr6-152805889; COSMIC: COSV54967679; COSMIC: COSV54967679;