6-152148053-C-G

Variant names:

• chr6-152148053-C-G
• rs2252755
• NM_182961.4:c.24968G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.24968G>C​(p.Gly8323Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,612,836 control chromosomes in the GnomAD database, including 95,907 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10833 hom., cov: 32)
  • Exomes 𝑓: 0.34 (85074 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.44
• Publications: 37 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: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002656132).
• BP6: Variant 6-152148053-C-G is Benign according to our data. Variant chr6-152148053-C-G is described in ClinVar as Benign. ClinVar VariationId is 130428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.461 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.24968G>C	p.Gly8323Ala	missense	Exon 137 of 146	NP_892006.3
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.1433G>C	p.Gly478Ala	missense	Exon 8 of 18	NP_001334631.1
	SYNE1	NM_033071.5		c.24755G>C	p.Gly8252Ala	missense	Exon 136 of 146	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.24968G>C	p.Gly8323Ala	missense	Exon 137 of 146	ENSP00000356224.5
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.1433G>C	p.Gly478Ala	missense	Exon 8 of 18	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.24755G>C	p.Gly8252Ala	missense	Exon 136 of 146	ENSP00000396024.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56203 AN: 151872 Hom.: 10817 Cov.: 32

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.364 AC: 90595 AN: 248750 AF XY: 0.360

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.302

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.337 AC: 492651 AN: 1460846 Hom.: 85074 Cov.: 35 AF XY: 0.339 AC XY: 246259 AN XY: 726722

African (AFR) AF: 0.436 AC: 14605 AN: 33468

American (AMR) AF: 0.506 AC: 22614 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 10842 AN: 26122

East Asian (EAS) AF: 0.310 AC: 12314 AN: 39694

South Asian (SAS) AF: 0.415 AC: 35786 AN: 86220

European-Finnish (FIN) AF: 0.222 AC: 11814 AN: 53140

Middle Eastern (MID) AF: 0.413 AC: 2383 AN: 5766

European-Non Finnish (NFE) AF: 0.325 AC: 361089 AN: 1111380

Other (OTH) AF: 0.351 AC: 21204 AN: 60364

GnomAD4 genome AF: 0.370 AC: 56270 AN: 151990 Hom.: 10833 Cov.: 32 AF XY: 0.370 AC XY: 27503 AN XY: 74290

African (AFR) AF: 0.441 AC: 18245 AN: 41410

American (AMR) AF: 0.470 AC: 7186 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1432 AN: 3470

East Asian (EAS) AF: 0.313 AC: 1613 AN: 5160

South Asian (SAS) AF: 0.407 AC: 1958 AN: 4814

European-Finnish (FIN) AF: 0.216 AC: 2289 AN: 10588

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22292 AN: 67952

Other (OTH) AF: 0.410 AC: 865 AN: 2110

Alfa AF: 0.340 Hom.: 6658

Bravo AF: 0.393

TwinsUK AF: 0.340 AC: 1259

ALSPAC AF: 0.330 AC: 1271

ESP6500AA AF: 0.444 AC: 1958

ESP6500EA AF: 0.337 AC: 2901

ExAC AF: 0.358 AC: 43517

Asia WGS AF: 0.372 AC: 1292 AN: 3478

EpiCase AF: 0.336

EpiControl AF: 0.340

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	0.090
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.23
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	N
PhyloP100		3.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.036
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.70	P
Vest4		0.26
MPC		0.16
ClinPred		0.046	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.32
Mutation Taster		=87/13	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2252755; hg19: chr6-152469188; COSMIC: COSV54911316; COSMIC: COSV54911316;