chr6-152390260-T-A

Variant names:

• chr6-152390260-T-A
• rs214943
• NM_182961.4:c.8177+20A>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.8177+20A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,612,516 control chromosomes in the GnomAD database, including 140,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (19389 hom., cov: 31)
  • Exomes 𝑓: 0.40 (121055 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.781
• Publications: 12 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=-0.86).
• BP6: Variant 6-152390260-T-A is Benign according to our data. Variant chr6-152390260-T-A is described in ClinVar as Benign. ClinVar VariationId is 262201.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.8177+20A>T		intron	N/A	NP_892006.3
	SYNE1	NM_033071.5		c.8198+20A>T		intron	N/A	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.8177+20A>T		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.8198+20A>T		intron	N/A	ENSP00000396024.1
	SYNE1	ENST00000461872.6	TSL:1	n.8395+20A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72910 AN: 151760 Hom.: 19366 Cov.: 31

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.466

GnomAD2 exomes AF: 0.432 AC: 108251 AN: 250648 AF XY: 0.432

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.769

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.396 AC: 579075 AN: 1460640 Hom.: 121055 Cov.: 35 AF XY: 0.399 AC XY: 289914 AN XY: 726652

African (AFR) AF: 0.702 AC: 23443 AN: 33394

American (AMR) AF: 0.308 AC: 13775 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9508 AN: 26130

East Asian (EAS) AF: 0.771 AC: 30586 AN: 39678

South Asian (SAS) AF: 0.484 AC: 41766 AN: 86240

European-Finnish (FIN) AF: 0.390 AC: 20818 AN: 53360

Middle Eastern (MID) AF: 0.470 AC: 2614 AN: 5564

European-Non Finnish (NFE) AF: 0.370 AC: 410780 AN: 1111268

Other (OTH) AF: 0.428 AC: 25785 AN: 60302

GnomAD4 genome AF: 0.481 AC: 72984 AN: 151876 Hom.: 19389 Cov.: 31 AF XY: 0.482 AC XY: 35738 AN XY: 74216

African (AFR) AF: 0.695 AC: 28791 AN: 41406

American (AMR) AF: 0.367 AC: 5595 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1320 AN: 3466

East Asian (EAS) AF: 0.755 AC: 3874 AN: 5130

South Asian (SAS) AF: 0.504 AC: 2432 AN: 4824

European-Finnish (FIN) AF: 0.382 AC: 4020 AN: 10534

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25561 AN: 67946

Other (OTH) AF: 0.466 AC: 982 AN: 2108

Alfa AF: 0.319 Hom.: 1276

Bravo AF: 0.488

Asia WGS AF: 0.600 AC: 2087 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.1
DANN	Benign	0.52
PhyloP100		0.78
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: rs214943; hg19: chr6-152711395; COSMIC: COSV54945465;