dbSNP rs372990463: SYNE1:p.Ala7902Pro (chr6-152164249-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182961.4(SYNE1):c.23704G>C(p.Ala7902Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7902T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Variant links:

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]

SYNE1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.23704G>C	p.Ala7902Pro	missense_variant	Exon 131 of 146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2 link	c.169G>C	p.Ala57Pro	missense_variant	Exon 2 of 18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 link	c.23704G>C	p.Ala7902Pro	missense_variant	Exon 131 of 146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1
SYNE1	ENST00000354674.5 link	c.169G>C	p.Ala57Pro	missense_variant	Exon 2 of 18	5	NM_001347702.2	ENSP00000346701.4		F8WAI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251298

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.;.;T;T;T;T

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.50

T;T;T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.;.

PhyloP100

1.6

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.7

D;.;D;D;D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0020

D;.;D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.81

MutPred

0.43

Loss of stability (P = 0.0518);.;.;.;.;.;.;

MVP

0.63

MPC

0.43

ClinPred

0.91

GERP RS

3.4

Varity_R

0.73

gMVP

0.67

Mutation Taster

=80/20

polymorphism

(source)

Splicing

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

Publications

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rs372990463

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over