rs104893936

Variant names:

• chr5-176626472-C-G
• rs104893936
• NM_003085.5:c.208G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-176626472-C-G
• chr5-176626472-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_003085.5(SNCB):​c.208G>C​(p.Val70Leu) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V70M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNCB NM_003085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 28 publications found

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: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-176626472-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7025.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCB	NM_003085.5	MANE Select	c.208G>C	p.Val70Leu	missense	Exon 4 of 6	NP_003076.1
	SNCB	NM_001001502.3		c.208G>C	p.Val70Leu	missense	Exon 5 of 7	NP_001001502.1
	SNCB	NM_001363140.2		c.208G>C	p.Val70Leu	missense	Exon 5 of 7	NP_001350069.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCB	ENST00000393693.7	TSL:1 MANE Select	c.208G>C	p.Val70Leu	missense	Exon 4 of 6	ENSP00000377296.2
	SNCB	ENST00000310112.7	TSL:1	c.208G>C	p.Val70Leu	missense	Exon 5 of 7	ENSP00000308057.3
	SNCB	ENST00000614675.4	TSL:1	c.166G>C	p.Val56Leu	missense	Exon 4 of 6	ENSP00000479489.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.085	T
Polyphen		0.045	B
Vest4		0.35
MutPred		0.87		Loss of helix (P = 0.1706)
MVP		0.72
MPC		0.61
ClinPred		0.43	T
GERP RS		2.6
Varity_R		0.24
gMVP		0.46
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs104893936; hg19: chr5-176053473;