NM_182961.4:c.2098-29C>T

Variant names:

• chr6-152462919-G-A
• rs7775181
• NM_182961.4:c.2098-29C>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.2098-29C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,612,170 control chromosomes in the GnomAD database, including 19,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3049 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16739 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.650
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-152462919-G-A is Benign according to our data. Variant chr6-152462919-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.2098-29C>T		intron_variant	Intron 19 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.2098-29C>T		intron_variant	Intron 19 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27363 AN: 151858 Hom.: 3053 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.159 AC: 39769 AN: 249602 AF XY: 0.160

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.0748

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.138 AC: 200821 AN: 1460196 Hom.: 16739 Cov.: 32 AF XY: 0.139 AC XY: 100910 AN XY: 726466

African (AFR) AF: 0.287 AC: 9604 AN: 33430

American (AMR) AF: 0.0794 AC: 3549 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3826 AN: 26118

East Asian (EAS) AF: 0.426 AC: 16912 AN: 39672

South Asian (SAS) AF: 0.191 AC: 16430 AN: 86222

European-Finnish (FIN) AF: 0.157 AC: 8301 AN: 52960

Middle Eastern (MID) AF: 0.137 AC: 790 AN: 5756

European-Non Finnish (NFE) AF: 0.119 AC: 131962 AN: 1111002

Other (OTH) AF: 0.157 AC: 9447 AN: 60338

GnomAD4 genome AF: 0.180 AC: 27384 AN: 151974 Hom.: 3049 Cov.: 32 AF XY: 0.184 AC XY: 13636 AN XY: 74240

African (AFR) AF: 0.285 AC: 11804 AN: 41416

American (AMR) AF: 0.120 AC: 1827 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 551 AN: 3468

East Asian (EAS) AF: 0.429 AC: 2206 AN: 5144

South Asian (SAS) AF: 0.208 AC: 1002 AN: 4824

European-Finnish (FIN) AF: 0.153 AC: 1611 AN: 10534

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7839 AN: 68010

Other (OTH) AF: 0.166 AC: 350 AN: 2108

Alfa AF: 0.101 Hom.: 219

Bravo AF: 0.182

Asia WGS AF: 0.293 AC: 1018 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.89
CADD	Benign	5.8
DANN	Benign	0.74
PhyloP100		-0.65
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: rs7775181; hg19: chr6-152784054; COSMIC: COSV54993287; COSMIC: COSV54993287;