6-152391617-C-T

Variant names:

• chr6-152391617-C-T
• rs214944
• NM_182961.4:c.7713-49G>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.7713-49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,482,530 control chromosomes in the GnomAD database, including 126,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18598 hom., cov: 27)
  • Exomes 𝑓: 0.39 (107777 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.471
• 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=-0.89).
• BP6: Variant 6-152391617-C-T is Benign according to our data. Variant chr6-152391617-C-T is described in ClinVar as Benign. ClinVar VariationId is 262200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.7713-49G>A		intron_variant	Intron 51 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.7713-49G>A		intron_variant	Intron 51 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.7734-49G>A		intron_variant	Intron 51 of 145	1		ENSP00000396024.1
SYNE1	ENST00000461872.6	n.7931-49G>A		intron_variant	Intron 49 of 54	1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 70838 AN: 149384 Hom.: 18577 Cov.: 27

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.368 AC: 44660 AN: 121384 AF XY: 0.368

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.747

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.385 AC: 513482 AN: 1333032 Hom.: 107777 Cov.: 28 AF XY: 0.386 AC XY: 254023 AN XY: 657354

African (AFR) AF: 0.691 AC: 20099 AN: 29104

American (AMR) AF: 0.270 AC: 8520 AN: 31578

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 8001 AN: 23108

East Asian (EAS) AF: 0.771 AC: 26353 AN: 34190

South Asian (SAS) AF: 0.463 AC: 32868 AN: 70998

European-Finnish (FIN) AF: 0.358 AC: 12331 AN: 34472

Middle Eastern (MID) AF: 0.447 AC: 1713 AN: 3828

European-Non Finnish (NFE) AF: 0.362 AC: 380615 AN: 1050646

Other (OTH) AF: 0.417 AC: 22982 AN: 55108

GnomAD4 genome AF: 0.474 AC: 70907 AN: 149498 Hom.: 18598 Cov.: 27 AF XY: 0.474 AC XY: 34504 AN XY: 72726

African (AFR) AF: 0.684 AC: 27686 AN: 40478

American (AMR) AF: 0.359 AC: 5384 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1314 AN: 3458

East Asian (EAS) AF: 0.752 AC: 3778 AN: 5022

South Asian (SAS) AF: 0.500 AC: 2353 AN: 4706

European-Finnish (FIN) AF: 0.365 AC: 3629 AN: 9944

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.376 AC: 25400 AN: 67626

Other (OTH) AF: 0.461 AC: 959 AN: 2082

Alfa AF: 0.359 Hom.: 3816

Bravo AF: 0.485

Asia WGS AF: 0.598 AC: 2081 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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. -

Arthrogryposis multiplex congenita 3, myogenic type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Jul 15, 2021

Genome-Nilou Lab

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	-0.89
CADD	Benign	2.5
DANN	Benign	0.56
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: rs214944; hg19: chr6-152712752; COSMIC: COSV107319828;