chr4-89726643-G-A

Variant names:

• chr4-89726643-G-A
• rs76642636
• NM_000345.4:c.408C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000345.4(SNCA):​c.408C>T​(p.Tyr136Tyr) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0100
• Publications: 11 publications found

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]

SNCA Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• autosomal dominant Parkinson disease 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Lewy body dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parkinsonian-pyramidal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251095 (HGNC:53614):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 350104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.01 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000345.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	NM_000345.4	MANE Select	c.408C>T	p.Tyr136Tyr	synonymous	Exon 6 of 6	NP_000336.1	P37840-1
	SNCA	NM_001146054.2		c.408C>T	p.Tyr136Tyr	synonymous	Exon 6 of 6	NP_001139526.1	P37840-1
	SNCA	NM_001146055.2		c.408C>T	p.Tyr136Tyr	synonymous	Exon 6 of 6	NP_001139527.1	P37840-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	ENST00000394991.8	TSL:1 MANE Select	c.408C>T	p.Tyr136Tyr	synonymous	Exon 6 of 6	ENSP00000378442.4	P37840-1
	SNCA	ENST00000394986.5	TSL:1	c.408C>T	p.Tyr136Tyr	synonymous	Exon 6 of 6	ENSP00000378437.1	P37840-1
	SNCA	ENST00000394989.6	TSL:1	c.366C>T	p.Tyr122Tyr	synonymous	Exon 5 of 5	ENSP00000378440.2	P37840-3

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00217 AC: 542 AN: 250202 AF XY: 0.00219

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00233 AC: 3401 AN: 1457904 Hom.: 7 Cov.: 27 AF XY: 0.00232 AC XY: 1682 AN XY: 725622

African (AFR) AF: 0.000450 AC: 15 AN: 33368

American (AMR) AF: 0.000448 AC: 20 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000996 AC: 26 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86184

European-Finnish (FIN) AF: 0.00405 AC: 216 AN: 53366

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.00267 AC: 2958 AN: 1108500

Other (OTH) AF: 0.00212 AC: 128 AN: 60278

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00245 AC XY: 182 AN XY: 74434

African (AFR) AF: 0.000481 AC: 20 AN: 41554

American (AMR) AF: 0.000851 AC: 13 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00428 AC: 291 AN: 68008

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00329 Hom.: 0

Bravo AF: 0.00192

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Lewy body dementia;C1854182:Autosomal dominant Parkinson disease 4;C1868595:Autosomal dominant Parkinson disease 1 (1)
-	-	1	Lewy body dementia;C1868595:Autosomal dominant Parkinson disease 1 (1)
-	-	1	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.4
DANN	Benign	0.81
PhyloP100		0.010
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs76642636; hg19: chr4-90647794; COSMIC: COSV61134973; COSMIC: COSV61134973;