rs202149617

Variant names:

• chr6-152471727-A-G
• rs202149617
• NM_182961.4:c.1502T>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_182961.4(SYNE1):​c.1502T>C​(p.Met501Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.86

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050576925).
• BS2: High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.1502T>C	p.Met501Thr	missense_variant	Exon 16 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.1502T>C	p.Met501Thr	missense_variant	Exon 16 of 146	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251120 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461610 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 508 of the SYNE1 protein (p.Met508Thr). This variant is present in population databases (rs202149617, gnomAD 0.1%). 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: 287465). 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 C0"). 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. -

not provided Uncertain:1

Apr 08, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0026	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.25	T;.;T;.;.;.;T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.051	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	N;.;.;N;.;N;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N;.;N;D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.13	T;.;T;T;T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;.
Polyphen		0.12	B;.;.;.;B;.;B;B;.
Vest4		0.38
MutPred		0.35		Loss of stability (P = 0.0134);.;.;Loss of stability (P = 0.0134);.;Loss of stability (P = 0.0134);.;Loss of stability (P = 0.0134);.;
MVP		0.77
MPC		0.15
ClinPred		0.060	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.27

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs202149617; hg19: chr6-152792862;