chr6-152152046-T-C

Variant names:

• chr6-152152046-T-C
• rs910415
• NM_182961.4:c.24225A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182961.4(SYNE1):​c.24225A>G​(p.Ala8075Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,614,170 control chromosomes in the GnomAD database, including 1,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A8075A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.047 (193 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1415 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.02
• 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: 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

ENSG00000300811 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-152152046-T-C is Benign according to our data. Variant chr6-152152046-T-C is described in ClinVar as Benign. ClinVar VariationId is 130425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0593 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.24225A>G	p.Ala8075Ala	synonymous	Exon 134 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.690A>G	p.Ala230Ala	synonymous	Exon 5 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.24012A>G	p.Ala8004Ala	synonymous	Exon 133 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.24225A>G	p.Ala8075Ala	synonymous	Exon 134 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.690A>G	p.Ala230Ala	synonymous	Exon 5 of 18	ENSP00000346701.4	F8WAI0
	SYNE1	ENST00000423061.6	TSL:1	c.24012A>G	p.Ala8004Ala	synonymous	Exon 133 of 146	ENSP00000396024.1	A0A0C4DG40

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 7185 AN: 152168 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0519

Gnomad ASJ AF: 0.0928

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.0427

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0414

Gnomad OTH AF: 0.0593

GnomAD2 exomes AF: 0.0397 AC: 9975 AN: 251452 AF XY: 0.0390

Gnomad AFR exome AF: 0.0623

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0881

Gnomad EAS exome AF: 0.000816

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0444

Gnomad OTH exome AF: 0.0487

GnomAD4 exome AF: 0.0410 AC: 59956 AN: 1461884 Hom.: 1415 Cov.: 32 AF XY: 0.0404 AC XY: 29392 AN XY: 727244

African (AFR) AF: 0.0621 AC: 2078 AN: 33480

American (AMR) AF: 0.0356 AC: 1593 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 2439 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0191 AC: 1646 AN: 86258

European-Finnish (FIN) AF: 0.0438 AC: 2339 AN: 53416

Middle Eastern (MID) AF: 0.0537 AC: 310 AN: 5768

European-Non Finnish (NFE) AF: 0.0420 AC: 46697 AN: 1112008

Other (OTH) AF: 0.0470 AC: 2841 AN: 60394

GnomAD4 genome AF: 0.0473 AC: 7206 AN: 152286 Hom.: 193 Cov.: 32 AF XY: 0.0470 AC XY: 3501 AN XY: 74468

African (AFR) AF: 0.0613 AC: 2547 AN: 41550

American (AMR) AF: 0.0517 AC: 791 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 322 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4828

European-Finnish (FIN) AF: 0.0427 AC: 453 AN: 10612

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0414 AC: 2817 AN: 68022

Other (OTH) AF: 0.0624 AC: 132 AN: 2114

Alfa AF: 0.0441 Hom.: 451

Bravo AF: 0.0482

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.0454

EpiControl AF: 0.0501

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.039
DANN	Benign	0.26
PhyloP100		-3.0
PromoterAI		0.00070	Neutral
Mutation Taster		=97/3	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs910415; hg19: chr6-152473181;