NM_182961.4:c.22910G>C

Variant names:

• chr6-152206277-C-G
• rs201497427
• NM_182961.4:c.22910G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_182961.4(SYNE1):​c.22910G>C​(p.Ser7637Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 2.63
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008820742).
• BP6: Variant 6-152206277-C-G is Benign according to our data. Variant chr6-152206277-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290926.

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.22910G>C	p.Ser7637Thr	missense	Exon 126 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.22697G>C	p.Ser7566Thr	missense	Exon 125 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.22910G>C	p.Ser7637Thr	missense	Exon 126 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.22697G>C	p.Ser7566Thr	missense	Exon 125 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000367251.7	TSL:1	c.1676G>C	p.Ser559Thr	missense	Exon 11 of 31	ENSP00000356220.3	H0Y325

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000271 AC: 68 AN: 251146 AF XY: 0.000287

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000164 AC: 239 AN: 1461628 Hom.: 0 Cov.: 32 AF XY: 0.000171 AC XY: 124 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00425 AC: 111 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.0000935 AC: 104 AN: 1111992

Other (OTH) AF: 0.000282 AC: 17 AN: 60378

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41600

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000490 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.028
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.073
Sift	Benign	0.54	T
Sift4G	Uncertain	0.021	D
Polyphen		0.86	P
Vest4		0.46
MVP		0.47
MPC		0.12
ClinPred		0.066	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.11
Mutation Taster		=82/18	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs201497427; hg19: chr6-152527412;