chr6-152310898-G-A

Variant names:

• chr6-152310898-G-A
• rs1538
• NM_182961.4:c.16711-25C>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.16711-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,608,712 control chromosomes in the GnomAD database, including 1,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.027 (106 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1079 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.959
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, PanelApp Australia, G2P
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-152310898-G-A is Benign according to our data. Variant chr6-152310898-G-A is described in ClinVar as Benign. ClinVar VariationId is 262170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.16711-25C>T		intron	N/A	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.16498-25C>T		intron	N/A	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.16711-25C>T		intron	N/A	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.16498-25C>T		intron	N/A	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000409694.6	TSL:1	n.270C>T		non_coding_transcript_exon	Exon 1 of 59

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4160 AN: 152114 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0422

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.0369 AC: 9035 AN: 244862 AF XY: 0.0354

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0460

Gnomad ASJ exome AF: 0.00484

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.0429

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0339

GnomAD4 exome AF: 0.0304 AC: 44345 AN: 1456480 Hom.: 1079 Cov.: 31 AF XY: 0.0297 AC XY: 21553 AN XY: 724494

African (AFR) AF: 0.0107 AC: 358 AN: 33404

American (AMR) AF: 0.0449 AC: 1992 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00484 AC: 126 AN: 26050

East Asian (EAS) AF: 0.151 AC: 6008 AN: 39660

South Asian (SAS) AF: 0.0178 AC: 1520 AN: 85620

European-Finnish (FIN) AF: 0.0425 AC: 2236 AN: 52642

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5756

European-Non Finnish (NFE) AF: 0.0273 AC: 30251 AN: 1108822

Other (OTH) AF: 0.0304 AC: 1832 AN: 60182

GnomAD4 genome AF: 0.0273 AC: 4162 AN: 152232 Hom.: 106 Cov.: 32 AF XY: 0.0282 AC XY: 2097 AN XY: 74430

African (AFR) AF: 0.0132 AC: 548 AN: 41542

American (AMR) AF: 0.0269 AC: 411 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.135 AC: 699 AN: 5172

South Asian (SAS) AF: 0.0263 AC: 127 AN: 4824

European-Finnish (FIN) AF: 0.0422 AC: 448 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0274 AC: 1861 AN: 68010

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0242 Hom.: 26

Bravo AF: 0.0269

Asia WGS AF: 0.0790 AC: 272 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.8
DANN	Benign	0.68
PhyloP100		0.96
BranchPoint Hunter		2.0
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: rs1538; hg19: chr6-152632033; COSMIC: COSV54935607; COSMIC: COSV54935607;