6-152419598-C-G

Variant names:

• chr6-152419598-C-G
• rs772266857
• NM_182961.4:c.5392G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182961.4(SYNE1):​c.5392G>C​(p.Asp1798His) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 150,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.5392G>C	p.Asp1798His	missense_variant	Exon 40 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.5392G>C	p.Asp1798His	missense_variant	Exon 40 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.5413G>C	p.Asp1805His	missense_variant	Exon 40 of 146	1		ENSP00000396024.1
SYNE1	ENST00000461872.6	n.5610G>C		non_coding_transcript_exon_variant	Exon 38 of 55	1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

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: 0.000481

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150912 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73548

Gnomad4 AFR AF: 0.0000487

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000481

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 05, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.70
DEOGEN2	Uncertain	0.69	D;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D;.;D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.76
MutPred		0.41		Loss of stability (P = 0.0994);.;.;
MVP		0.53
MPC		0.63
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.61
gMVP		0.33

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs772266857; hg19: chr6-152740733;