5-176620840-C-T

Variant names:

• chr5-176620840-C-T
• rs1759538365
• NM_003085.5:c.376G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003085.5(SNCB):​c.376G>A​(p.Glu126Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SNCB NM_003085.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28724867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCB	NM_003085.5	c.376G>A	p.Glu126Lys	missense_variant	Exon 6 of 6	ENST00000393693.7	NP_003076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCB	ENST00000393693.7	c.376G>A	p.Glu126Lys	missense_variant	Exon 6 of 6	1	NM_003085.5	ENSP00000377296.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461604 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376G>A (p.E126K) alteration is located in exon 7 (coding exon 5) of the SNCB gene. This alteration results from a G to A substitution at nucleotide position 376, causing the glutamic acid (E) at amino acid position 126 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D;T;D;D;D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	.;T;.;.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.6	L;.;L;L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.42	N;.;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.22	T;.;T;T;T
Sift4G	Uncertain	0.026	D;D;D;D;D
Polyphen		0.95	P;.;P;P;P
Vest4		0.30
MutPred		0.45		Gain of methylation at E126 (P = 0.0013);.;Gain of methylation at E126 (P = 0.0013);Gain of methylation at E126 (P = 0.0013);Gain of methylation at E126 (P = 0.0013);
MVP		0.88
MPC		0.58
ClinPred		0.79	D
GERP RS		3.3
Varity_R		0.11
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1759538365; hg19: chr5-176047841;