rs34891041

Variant names:

• chr6-152213633-C-T
• rs34891041
• NM_182961.4:c.22473G>A

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.22473G>A​(p.Leu7491Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,613,978 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (91 hom., cov: 32)
  • Exomes 𝑓: 0.028 (690 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.417
• Publications: 3 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: G2P, Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, 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: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• 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=-0.26).
• BP6: Variant 6-152213633-C-T is Benign according to our data. Variant chr6-152213633-C-T is described in ClinVar as Benign. ClinVar VariationId is 130421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.417 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.031 (4722/152214) while in subpopulation AFR AF = 0.047 (1952/41538). AF 95% confidence interval is 0.0453. There are 91 homozygotes in GnomAd4. There are 2222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 91 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.22473G>A	p.Leu7491Leu	synonymous	Exon 123 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.22260G>A	p.Leu7420Leu	synonymous	Exon 122 of 146	NP_149062.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.22473G>A	p.Leu7491Leu	synonymous	Exon 123 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.22260G>A	p.Leu7420Leu	synonymous	Exon 122 of 146	ENSP00000396024.1
	SYNE1	ENST00000367251.7	TSL:1	c.1239G>A	p.Leu413Leu	synonymous	Exon 8 of 31	ENSP00000356220.3

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4710 AN: 152096 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00927

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0241 AC: 6055 AN: 251424 AF XY: 0.0229

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.00945

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00701

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0280 AC: 40858 AN: 1461764 Hom.: 690 Cov.: 33 AF XY: 0.0271 AC XY: 19715 AN XY: 727198

African (AFR) AF: 0.0482 AC: 1612 AN: 33474

American (AMR) AF: 0.0102 AC: 457 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 307 AN: 26130

East Asian (EAS) AF: 0.00824 AC: 327 AN: 39684

South Asian (SAS) AF: 0.00677 AC: 584 AN: 86254

European-Finnish (FIN) AF: 0.0351 AC: 1875 AN: 53420

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0307 AC: 34113 AN: 1111920

Other (OTH) AF: 0.0258 AC: 1556 AN: 60392

GnomAD4 genome AF: 0.0310 AC: 4722 AN: 152214 Hom.: 91 Cov.: 32 AF XY: 0.0299 AC XY: 2222 AN XY: 74434

African (AFR) AF: 0.0470 AC: 1952 AN: 41538

American (AMR) AF: 0.0180 AC: 275 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 47 AN: 3468

East Asian (EAS) AF: 0.00929 AC: 48 AN: 5168

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4820

European-Finnish (FIN) AF: 0.0332 AC: 352 AN: 10590

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0287 AC: 1951 AN: 68018

Other (OTH) AF: 0.0322 AC: 68 AN: 2112

Alfa AF: 0.0308 Hom.: 150

Bravo AF: 0.0308

Asia WGS AF: 0.0290 AC: 100 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0260

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	5.2
DANN	Benign	0.78
PhyloP100		0.42
Mutation Taster		=96/4	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs34891041; hg19: chr6-152534768;