chr3-121114952-G-C

Variant names:

• chr3-121114952-G-C
• rs778361831
• NM_001308330.2:c.498G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001308330.2(STXBP5L):​c.498G>C​(p.Gln166His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,504 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: STXBP5L NM_001308330.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01

Genes affected

STXBP5L (HGNC:30757): (syntaxin binding protein 5L) The protein encoded by this gene is similar to syntaxin-binding protein 5 and contains ten N-terminal WD40 repeats, four variable region WD40 repeats, and a C-terminal R-SNARE domain. Studies of the orthologous proteins in mouse and rat have shown that the encoded protein may inhibit exocytosis in neurosecretory cells, and may negatively regulate the secretion of insulin. A missense variant in this gene is likely the cause of an infantile-onset neurodegenerative disorder diagnosed in two siblings of consanguineous parents. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP5L	NM_001308330.2	c.498G>C	p.Gln166His	missense_variant	Exon 6 of 27	ENST00000471454.6	NP_001295259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP5L	ENST00000471454.6	c.498G>C	p.Gln166His	missense_variant	Exon 6 of 27	2	NM_001308330.2	ENSP00000420019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000458 AC: 1 AN: 218284 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 119094

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000988

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424504 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 707354

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: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T;T;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.55	D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.014	D;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.98	D;D;.;.;.;.
Vest4		0.67
MutPred		0.50		Gain of ubiquitination at K168 (P = 0.0898);Gain of ubiquitination at K168 (P = 0.0898);Gain of ubiquitination at K168 (P = 0.0898);Gain of ubiquitination at K168 (P = 0.0898);Gain of ubiquitination at K168 (P = 0.0898);Gain of ubiquitination at K168 (P = 0.0898);
MVP		0.34
MPC		0.60
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.37
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs778361831; hg19: chr3-120833799;