NM_182961.4:c.22516A>G

Variant names:

• chr6-152211567-T-C
• rs35763277
• NM_182961.4:c.22516A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182961.4(SYNE1):​c.22516A>G​(p.Ser7506Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,628 control chromosomes in the GnomAD database, including 268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 32)
  • Exomes 𝑓: 0.016 (249 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.89
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009470105).
• BP6: Variant 6-152211567-T-C is Benign according to our data. Variant chr6-152211567-T-C is described in ClinVar as Benign. ClinVar VariationId is 130422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1704/152292) while in subpopulation NFE AF = 0.0161 (1096/68024). AF 95% confidence interval is 0.0153. There are 19 homozygotes in GnomAd4. There are 851 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.22516A>G	p.Ser7506Gly	missense	Exon 124 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.22303A>G	p.Ser7435Gly	missense	Exon 123 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.22516A>G	p.Ser7506Gly	missense	Exon 124 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.22303A>G	p.Ser7435Gly	missense	Exon 123 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000367251.7	TSL:1	c.1282A>G	p.Ser428Gly	missense	Exon 9 of 31	ENSP00000356220.3	H0Y325

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1704 AN: 152176 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0293

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0127 AC: 3183 AN: 250946 AF XY: 0.0123

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0158 AC: 23061 AN: 1461336 Hom.: 249 Cov.: 30 AF XY: 0.0153 AC XY: 11092 AN XY: 726984

African (AFR) AF: 0.00227 AC: 76 AN: 33468

American (AMR) AF: 0.00389 AC: 174 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00754 AC: 197 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00293 AC: 253 AN: 86220

European-Finnish (FIN) AF: 0.0276 AC: 1473 AN: 53350

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.0181 AC: 20101 AN: 1111650

Other (OTH) AF: 0.0128 AC: 775 AN: 60380

GnomAD4 genome AF: 0.0112 AC: 1704 AN: 152292 Hom.: 19 Cov.: 32 AF XY: 0.0114 AC XY: 851 AN XY: 74462

African (AFR) AF: 0.00284 AC: 118 AN: 41554

American (AMR) AF: 0.00752 AC: 115 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

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

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.0293 AC: 311 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0161 AC: 1096 AN: 68024

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0141 Hom.: 44

Bravo AF: 0.00978

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0171 AC: 147

ExAC AF: 0.0137 AC: 1660

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0152

EpiControl AF: 0.0159

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.41
Sift	Benign	0.060	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.73
MPC		0.57
ClinPred		0.011	T
GERP RS		5.6
Varity_R		0.36
gMVP		0.33
Mutation Taster		=74/26	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs35763277; hg19: chr6-152532702;