rs10499268

Variant names:

• chr6-152331464-G-A
• rs10499268
• NM_182961.4:c.13221C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152331464-G-A
• chr6-152331464-G-T

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.13221C>T​(p.Asp4407Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,614,068 control chromosomes in the GnomAD database, including 1,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (99 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1381 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.350
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 6-152331464-G-A is Benign according to our data. Variant chr6-152331464-G-A is described in ClinVar as Benign. ClinVar VariationId is 130403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0343 (5227/152204) while in subpopulation SAS AF = 0.0473 (228/4818). AF 95% confidence interval is 0.0423. There are 99 homozygotes in GnomAd4. There are 2472 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 99 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.13221C>T	p.Asp4407Asp	synonymous	Exon 78 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.13008C>T	p.Asp4336Asp	synonymous	Exon 77 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.13221C>T	p.Asp4407Asp	synonymous	Exon 78 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.13008C>T	p.Asp4336Asp	synonymous	Exon 77 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000490135.6	TSL:1	n.567C>T		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 5217 AN: 152086 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.0471

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.0312

GnomAD2 exomes AF: 0.0332 AC: 8352 AN: 251336 AF XY: 0.0348

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.0438

Gnomad EAS exome AF: 0.0229

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0414 AC: 60553 AN: 1461864 Hom.: 1381 Cov.: 83 AF XY: 0.0410 AC XY: 29815 AN XY: 727228

African (AFR) AF: 0.0305 AC: 1021 AN: 33480

American (AMR) AF: 0.0164 AC: 732 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0433 AC: 1131 AN: 26136

East Asian (EAS) AF: 0.0220 AC: 875 AN: 39700

South Asian (SAS) AF: 0.0435 AC: 3751 AN: 86252

European-Finnish (FIN) AF: 0.0152 AC: 810 AN: 53416

Middle Eastern (MID) AF: 0.0217 AC: 125 AN: 5768

European-Non Finnish (NFE) AF: 0.0446 AC: 49639 AN: 1111998

Other (OTH) AF: 0.0409 AC: 2469 AN: 60394

GnomAD4 genome AF: 0.0343 AC: 5227 AN: 152204 Hom.: 99 Cov.: 32 AF XY: 0.0332 AC XY: 2472 AN XY: 74410

African (AFR) AF: 0.0304 AC: 1264 AN: 41526

American (AMR) AF: 0.0194 AC: 297 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3470

East Asian (EAS) AF: 0.0201 AC: 104 AN: 5178

South Asian (SAS) AF: 0.0473 AC: 228 AN: 4818

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10590

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0423 AC: 2875 AN: 68020

Other (OTH) AF: 0.0308 AC: 65 AN: 2108

Alfa AF: 0.0382 Hom.: 219

Bravo AF: 0.0342

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0409

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	-0.57
CADD	Benign	0.19
DANN	Benign	0.42
PhyloP100		-0.35
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10499268; hg19: chr6-152652599; COSMIC: COSV54906521; COSMIC: COSV54906521;