5-176626411-G-A

Position:

• chr5-176626411-G-A

Variant summary

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

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.76

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]

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, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCB	NM_003085.5	c.269C>T	p.Pro90Leu	missense_variant	4/6	ENST00000393693.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCB	ENST00000393693.7	c.269C>T	p.Pro90Leu	missense_variant	4/6	1	NM_003085.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lewy body dementia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.269C>T (p.Pro90Leu) in the SNCB gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Proline at position 90 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Pro90Leu in SNCB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.72	D;D;D;D;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;.;D;D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.12	T;.;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T
Polyphen		1.0	D;.;D;D;D
Vest4		0.71
MutPred		0.51		Loss of ubiquitination at K85 (P = 0.037);.;Loss of ubiquitination at K85 (P = 0.037);Loss of ubiquitination at K85 (P = 0.037);Loss of ubiquitination at K85 (P = 0.037);
MVP		0.93
MPC		1.5
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.23
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-176053412;