rs7776344

Variant names:

• chr6-152462940-C-T
• rs7776344
• NM_182961.4:c.2098-50G>A

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.2098-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,600,770 control chromosomes in the GnomAD database, including 19,630 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 (3054 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16576 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.31
• 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=-0.8).
• BP6: Variant 6-152462940-C-T is Benign according to our data. Variant chr6-152462940-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262181.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.2098-50G>A		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.2098-50G>A		intron_variant	Intron 19 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27356 AN: 151848 Hom.: 3057 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: 39480 AN: 247682 AF XY: 0.160

Gnomad AFR exome AF: 0.285

Gnomad AMR exome AF: 0.0747

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: 0.137 AC: 198919 AN: 1448802 Hom.: 16576 Cov.: 29 AF XY: 0.139 AC XY: 100114 AN XY: 721626

African (AFR) AF: 0.287 AC: 9515 AN: 33176

American (AMR) AF: 0.0794 AC: 3546 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3812 AN: 26030

East Asian (EAS) AF: 0.426 AC: 16879 AN: 39618

South Asian (SAS) AF: 0.190 AC: 16366 AN: 85974

European-Finnish (FIN) AF: 0.157 AC: 8156 AN: 51922

Middle Eastern (MID) AF: 0.136 AC: 782 AN: 5732

European-Non Finnish (NFE) AF: 0.118 AC: 130510 AN: 1101772

Other (OTH) AF: 0.156 AC: 9353 AN: 59936

GnomAD4 genome AF: 0.180 AC: 27376 AN: 151968 Hom.: 3054 Cov.: 32 AF XY: 0.184 AC XY: 13641 AN XY: 74256

African (AFR) AF: 0.285 AC: 11813 AN: 41428

American (AMR) AF: 0.119 AC: 1821 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 552 AN: 3468

East Asian (EAS) AF: 0.429 AC: 2206 AN: 5148

South Asian (SAS) AF: 0.208 AC: 1002 AN: 4822

European-Finnish (FIN) AF: 0.153 AC: 1612 AN: 10556

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

European-Non Finnish (NFE) AF: 0.115 AC: 7828 AN: 67976

Other (OTH) AF: 0.165 AC: 348 AN: 2112

Alfa AF: 0.149 Hom.: 572

Bravo AF: 0.182

Asia WGS AF: 0.291 AC: 1010 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

not specified Benign:1

-

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	-0.80
CADD	Benign	1.5
DANN	Benign	0.55
PhyloP100		-1.3
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: rs7776344; hg19: chr6-152784075; COSMIC: COSV107318903; COSMIC: COSV107318903;