rs201346604

chr6-152262187-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_182961.4(SYNE1):c.18817G>A(p.Glu6273Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000133 in 1,613,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense, splice_region
• Scores: Splicing: ADA: 0.9765
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.15

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.18817G>A	p.Glu6273Lys	missense_variant, splice_region_variant	101/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.18817G>A	p.Glu6273Lys	missense_variant, splice_region_variant	101/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151956 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 29 AN: 251210 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135774

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1461288 Hom.: 0 Cov.: 30 AF XY: 0.000151 AC XY: 110 AN XY: 726970

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152074 Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74334

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 16, 2018	- -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 6202 of the SYNE1 protein (p.Glu6202Lys). This variant is present in population databases (rs201346604, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 538396). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.093
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.066	B;.;.
Vest4		0.50
MVP		0.54
MPC		0.17
ClinPred		0.036	T
GERP RS		6.0
Varity_R		0.20
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs201346604; hg19: chr6-152583322; COSMIC: COSV99569224;