Genetic Variant NM_003085.5:c.269C>T (chr5-176626411-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_003085.5(SNCB):c.269C>T(p.Pro90Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SNCB
NM_003085.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.76

Publications

0 publications found

Variant links:

Genes affected

SNCB (HGNC:11140): (synuclein beta) This gene encodes a member of a small family of proteins that inhibit phospholipase D2 and may function in neuronal plasticity. The encoded protein is abundant in lesions of patients with Alzheimer disease. A mutation in this gene was found in individuals with dementia with Lewy bodies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

SNCB Gene-Disease associations (from GenCC):

Lewy body dementia
Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics

SNCB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.95189 (below the threshold of 3.09). Trascript score misZ: 1.453 (below the threshold of 3.09). GenCC associations: The gene is linked to Lewy body dementia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SNCB	NM_003085.5	MANE Select	c.269C>T	p.Pro90Leu	missense	Exon 4 of 6	NP_003076.1	Q16143
SNCB	NM_001001502.3		c.269C>T	p.Pro90Leu	missense	Exon 5 of 7	NP_001001502.1	Q16143
SNCB	NM_001363140.2		c.269C>T	p.Pro90Leu	missense	Exon 5 of 7	NP_001350069.1	Q16143

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SNCB	ENST00000393693.7	TSL:1 MANE Select	c.269C>T	p.Pro90Leu	missense	Exon 4 of 6	ENSP00000377296.2	Q16143
SNCB	ENST00000310112.7	TSL:1	c.269C>T	p.Pro90Leu	missense	Exon 5 of 7	ENSP00000308057.3	Q16143
SNCB	ENST00000614675.4	TSL:1	c.227C>T	p.Pro76Leu	missense	Exon 4 of 6	ENSP00000479489.1	G4Y816

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lewy body dementia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.3

PhyloP100

6.8

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.66

Sift

Benign

0.12

Sift4G

Benign

0.69

Polyphen

1.0

Vest4

0.71

MutPred

0.51

Loss of ubiquitination at K85 (P = 0.037)

MVP

0.93

MPC

1.5

ClinPred

0.98

GERP RS

4.4

Varity_R

0.23

gMVP

0.51

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over