chr5-176626449-G-C

Position:

• chr5-176626449-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003085.5(SNCB):​c.231C>G​(p.Ile77Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: -0.543

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCB	NM_003085.5	c.231C>G	p.Ile77Met	missense_variant	4/6	ENST00000393693.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCB	ENST00000393693.7	c.231C>G	p.Ile77Met	missense_variant	4/6	1	NM_003085.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461756 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.231C>G (p.I77M) alteration is located in exon 5 (coding exon 3) of the SNCB gene. This alteration results from a C to G substitution at nucleotide position 231, causing the isoleucine (I) at amino acid position 77 to be replaced by a methionine (M). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;T;D;D;D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.33	N
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	1.5	L;.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N;.;N;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.043	D;.;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.96	D;.;D;D;D
Vest4		0.81
MutPred		0.70		Gain of disorder (P = 0.0249);.;Gain of disorder (P = 0.0249);Gain of disorder (P = 0.0249);Gain of disorder (P = 0.0249);
MVP		0.77
MPC		1.5
ClinPred		0.93	D
GERP RS		-0.89
Varity_R		0.24
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr5-176053450;