rs104893875

Variant names:

• chr4-89828170-C-G
• NM_000345.4:c.136G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-89828170-C-G
• chr4-89828170-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000345.4(SNCA):​c.136G>C​(p.Glu46Gln) variant causes a missense change. 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. E46K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNCA NM_000345.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.37

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest 4 X 11 AA tandem repeats of [EGS]-K-T-K-[EQ]-[GQ]-V-X(4) (size 47) in uniprot entity SYUA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000345.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-89828170-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.136G>C	p.Glu46Gln	missense_variant	Exon 3 of 6	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.136G>C	p.Glu46Gln	missense_variant	Exon 3 of 6	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.;D;D;D;D;.;D
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;.;.;.;.;.;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.6	L;L;L;L;L;L;L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.028	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.055	T;T;T;T;T;T;T;D;.
Polyphen		0.13	B;P;B;P;P;P;P;.;.
Vest4		0.37
MutPred		0.67		Gain of catalytic residue at E46 (P = 0.0199);Gain of catalytic residue at E46 (P = 0.0199);Gain of catalytic residue at E46 (P = 0.0199);Gain of catalytic residue at E46 (P = 0.0199);Gain of catalytic residue at E46 (P = 0.0199);Gain of catalytic residue at E46 (P = 0.0199);Gain of catalytic residue at E46 (P = 0.0199);Gain of catalytic residue at E46 (P = 0.0199);Gain of catalytic residue at E46 (P = 0.0199);
MVP		0.84
MPC		0.69
ClinPred		0.95	D
GERP RS		3.5
Varity_R		0.62
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr4-90749321;