rs36044575

Variant names:

• chr6-152213654-T-C
• rs36044575
• NM_182961.4:c.22452A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182961.4(SYNE1):​c.22452A>G​(p.Ser7484Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,614,110 control chromosomes in the GnomAD database, including 944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (84 hom., cov: 32)
  • Exomes 𝑓: 0.029 (860 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.593
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-152213654-T-C is Benign according to our data. Variant chr6-152213654-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.593 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0245 (3738/152318) while in subpopulation NFE AF = 0.0332 (2257/68026). AF 95% confidence interval is 0.032. There are 84 homozygotes in GnomAd4. There are 1987 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 84 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.22452A>G	p.Ser7484Ser	synonymous	Exon 123 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.22239A>G	p.Ser7413Ser	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.22452A>G	p.Ser7484Ser	synonymous	Exon 123 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.22239A>G	p.Ser7413Ser	synonymous	Exon 122 of 146	ENSP00000396024.1
	SYNE1	ENST00000367251.7	TSL:1	c.1218A>G	p.Ser406Ser	synonymous	Exon 8 of 31	ENSP00000356220.3

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3740 AN: 152200 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0915

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0332

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0260 AC: 6530 AN: 251398 AF XY: 0.0251

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.00986

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0907

Gnomad NFE exome AF: 0.0336

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0295 AC: 43074 AN: 1461792 Hom.: 860 Cov.: 33 AF XY: 0.0287 AC XY: 20895 AN XY: 727204

African (AFR) AF: 0.00442 AC: 148 AN: 33474

American (AMR) AF: 0.0110 AC: 492 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 151 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.00334 AC: 288 AN: 86256

European-Finnish (FIN) AF: 0.0883 AC: 4715 AN: 53418

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0323 AC: 35894 AN: 1111944

Other (OTH) AF: 0.0226 AC: 1366 AN: 60394

GnomAD4 genome AF: 0.0245 AC: 3738 AN: 152318 Hom.: 84 Cov.: 32 AF XY: 0.0267 AC XY: 1987 AN XY: 74468

African (AFR) AF: 0.00479 AC: 199 AN: 41566

American (AMR) AF: 0.0157 AC: 240 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0915 AC: 971 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0332 AC: 2257 AN: 68026

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0276 Hom.: 59

Bravo AF: 0.0175

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.66
DANN	Benign	0.77
PhyloP100		-0.59
Mutation Taster		=93/7	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs36044575; hg19: chr6-152534789;