rs60344647

Positions:

• chr6-152344168-C-G
• chr6-152344168-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_182961.4(SYNE1):​c.12138G>C​(p.Gln4046His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q4046Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNE1. . Gene score misZ -0.29069 (greater than the threshold 3.09). Trascript score misZ 3.2909 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive ataxia, Beauce type, autosomal recessive myogenic arthrogryposis multiplex congenita, Emery-Dreifuss muscular dystrophy 4, autosomal dominant, arthrogryposis multiplex congenita 3, myogenic type, autosomal dominant Emery-Dreifuss muscular dystrophy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.12138G>C	p.Gln4046His	missense_variant	74/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.12138G>C	p.Gln4046His	missense_variant	74/146	1	NM_182961.4	ENSP00000356224	P1
SYNE1	ENST00000423061.6	c.11925G>C	p.Gln3975His	missense_variant	73/146	1		ENSP00000396024
SYNE1	ENST00000471834.1	n.5276G>C		non_coding_transcript_exon_variant	17/19	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N;D;N
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.64
MutPred		0.29		Gain of catalytic residue at Q4046 (P = 0.0738);.;.;
MVP		0.40
MPC		0.55
ClinPred		0.95	D
GERP RS		2.0
Varity_R		0.23
gMVP		0.31

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs60344647; hg19: chr6-152665303;