6-152362262-C-T

Variant names:

• chr6-152362262-C-T
• rs116758271
• NM_182961.4:c.10207G>A

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.10207G>A​(p.Gly3403Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,614,176 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (21 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.46
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004250765).
• BP6: Variant 6-152362262-C-T is Benign according to our data. Variant chr6-152362262-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0121 (1840/152288) while in subpopulation AFR AF = 0.0418 (1736/41548). AF 95% confidence interval is 0.0401. There are 40 homozygotes in GnomAd4. There are 849 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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.10207G>A	p.Gly3403Ser	missense	Exon 64 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.10228G>A	p.Gly3410Ser	missense	Exon 64 of 146	NP_149062.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.10207G>A	p.Gly3403Ser	missense	Exon 64 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.10228G>A	p.Gly3410Ser	missense	Exon 64 of 146	ENSP00000396024.1
	SYNE1	ENST00000471834.1	TSL:1	n.3345G>A		non_coding_transcript_exon	Exon 7 of 19

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1838 AN: 152170 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00321 AC: 806 AN: 251478 AF XY: 0.00256

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00127 AC: 1853 AN: 1461888 Hom.: 21 Cov.: 30 AF XY: 0.00112 AC XY: 813 AN XY: 727244

African (AFR) AF: 0.0424 AC: 1421 AN: 33480

American (AMR) AF: 0.00226 AC: 101 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

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

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1112008

Other (OTH) AF: 0.00267 AC: 161 AN: 60396

GnomAD4 genome AF: 0.0121 AC: 1840 AN: 152288 Hom.: 40 Cov.: 33 AF XY: 0.0114 AC XY: 849 AN XY: 74468

African (AFR) AF: 0.0418 AC: 1736 AN: 41548

American (AMR) AF: 0.00483 AC: 74 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68028

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00312 Hom.: 11

Bravo AF: 0.0134

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0456 AC: 201

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00418 AC: 508

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.0
DANN	Benign	0.45
DEOGEN2	Benign	0.067	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N
PhyloP100		1.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.053
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.079
MVP		0.12
MPC		0.13
ClinPred		0.0017	T
GERP RS		-3.0
Varity_R		0.023
gMVP		0.067
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs116758271; hg19: chr6-152683397;