6-152244594-C-G

Variant names:

• chr6-152244594-C-G
• rs147143947
• NM_182961.4:c.19635G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182961.4(SYNE1):​c.19635G>C​(p.Arg6545Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.490

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054761857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.19635G>C	p.Arg6545Ser	missense_variant	Exon 106 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.19635G>C	p.Arg6545Ser	missense_variant	Exon 106 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.19422G>C	p.Arg6474Ser	missense_variant	Exon 105 of 146	1		ENSP00000396024.1
SYNE1	ENST00000367256.9	n.3327G>C		non_coding_transcript_exon_variant	Exon 21 of 61	1
SYNE1	ENST00000409694.6	n.3219G>C		non_coding_transcript_exon_variant	Exon 19 of 59	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 6474 of the SYNE1 protein (p.Arg6474Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. 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 C15"). 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	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.0
DANN	Benign	0.43
DEOGEN2	Benign	0.081	T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.075	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.61	N;.;N
REVEL	Benign	0.017
Sift	Benign	0.74	T;.;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.32
MutPred		0.39		Gain of phosphorylation at R6545 (P = 0.0357);.;.;
MVP		0.15
MPC		0.16
ClinPred		0.12	T
GERP RS		-3.5
Varity_R		0.092
gMVP		0.13

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs147143947; hg19: chr6-152565729;