rs76642636
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_000345.4(SNCA):c.408C>T(p.Tyr136=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,610,154 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0023 ( 7 hom. )
Consequence
SNCA
NM_000345.4 synonymous
NM_000345.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0100
Genes affected
SNCA (HGNC:11138): (synuclein alpha) Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer's disease. Alternatively spliced transcripts encoding different isoforms have been identified for this gene. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
Variant 4-89726643-G-A is Benign according to our data. Variant chr4-89726643-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 350104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-89726643-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.01 with no splicing effect.
BS2
High AC in GnomAd4 at 371 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SNCA | NM_000345.4 | c.408C>T | p.Tyr136= | synonymous_variant | 6/6 | ENST00000394991.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SNCA | ENST00000394991.8 | c.408C>T | p.Tyr136= | synonymous_variant | 6/6 | 1 | NM_000345.4 | P1 | |
ENST00000659878.1 | n.739G>A | non_coding_transcript_exon_variant | 3/3 |
Frequencies
GnomAD3 genomes AF: 0.00244 AC: 371AN: 152132Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00217 AC: 542AN: 250202Hom.: 2 AF XY: 0.00219 AC XY: 297AN XY: 135342
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GnomAD4 exome AF: 0.00233 AC: 3401AN: 1457904Hom.: 7 Cov.: 27 AF XY: 0.00232 AC XY: 1682AN XY: 725622
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GnomAD4 genome AF: 0.00244 AC: 371AN: 152250Hom.: 1 Cov.: 32 AF XY: 0.00245 AC XY: 182AN XY: 74434
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | SNCA: BP4, BP7, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2020 | - - |
Lewy body dementia;C1868595:Autosomal dominant Parkinson disease 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Parkinson Disease, Dominant Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Lewy body dementia;C1854182:Autosomal dominant Parkinson disease 4;C1868595:Autosomal dominant Parkinson disease 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 22, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at