rs62426382

Variant names:

• chr6-152358459-A-G
• rs62426382
• NM_182961.4:c.10522T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-152358459-A-G
• chr6-152358459-A-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_182961.4(SYNE1):​c.10522T>C​(p.Leu3508Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,614,024 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L3508L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (173 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.53
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 6-152358459-A-G is Benign according to our data. Variant chr6-152358459-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0141 (20623/1461868) while in subpopulation NFE AF = 0.0156 (17343/1111996). AF 95% confidence interval is 0.0154. There are 173 homozygotes in GnomAdExome4. There are 10003 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR,AD gene

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.10522T>C	p.Leu3508Leu	synonymous	Exon 66 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.10543T>C	p.Leu3515Leu	synonymous	Exon 66 of 146	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.10522T>C	p.Leu3508Leu	synonymous	Exon 66 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.10543T>C	p.Leu3515Leu	synonymous	Exon 66 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000471834.1	TSL:1	n.3660T>C		non_coding_transcript_exon	Exon 9 of 19

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1604 AN: 152038 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0110 AC: 2761 AN: 251480 AF XY: 0.0113

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.0413

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0141 AC: 20623 AN: 1461868 Hom.: 173 Cov.: 31 AF XY: 0.0138 AC XY: 10003 AN XY: 727236

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.00856 AC: 383 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 1035 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00219 AC: 189 AN: 86258

European-Finnish (FIN) AF: 0.0117 AC: 626 AN: 53418

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.0156 AC: 17343 AN: 1111996

Other (OTH) AF: 0.0157 AC: 949 AN: 60396

GnomAD4 genome AF: 0.0105 AC: 1603 AN: 152156 Hom.: 16 Cov.: 32 AF XY: 0.0101 AC XY: 749 AN XY: 74368

African (AFR) AF: 0.00272 AC: 113 AN: 41532

American (AMR) AF: 0.0110 AC: 168 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4814

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0148 AC: 1005 AN: 67982

Other (OTH) AF: 0.0114 AC: 24 AN: 2110

Alfa AF: 0.0141 Hom.: 10

Bravo AF: 0.0111

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0138

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	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)
-	-	1	SYNE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.7
DANN	Benign	0.73
PhyloP100		1.5
Mutation Taster		=97/3	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62426382; hg19: chr6-152679594;