4-4434855-T-C

Variant names:

• chr4-4434855-T-C
• rs764685617
• NM_016930.4:c.617A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016930.4(STX18):​c.617A>G​(p.Lys206Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 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. K206I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STX18 NM_016930.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

Genes affected

STX18 (HGNC:15942): (syntaxin 18) This gene encodes a member of the syntaxin family of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) which is part of a membrane tethering complex that includes other SNAREs and several peripheral membrane proteins, and is involved in vesicular transport between the endoplasmic reticulum (ER) and the Golgi complex. The encoded protein is important for the organization of the smooth, rough, and exit site ER subdomains. A pseudogene of this gene has been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016930.4. 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
	STX18	NM_016930.4	MANE Select	c.617A>G	p.Lys206Arg	missense	Exon 7 of 11	NP_058626.1	Q9P2W9
	STX18	NM_001346281.2		c.670A>G	p.Lys224Glu	missense	Exon 8 of 11	NP_001333210.1
	STX18	NM_001346282.2		c.374A>G	p.Lys125Arg	missense	Exon 7 of 11	NP_001333211.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX18	ENST00000306200.7	TSL:1 MANE Select	c.617A>G	p.Lys206Arg	missense	Exon 7 of 11	ENSP00000305810.2	Q9P2W9
	STX18	ENST00000505286.5	TSL:1	c.617A>G	p.Lys206Arg	missense	Exon 7 of 11	ENSP00000426648.1	D6RF48
	STX18	ENST00000963664.1		c.710A>G	p.Lys237Arg	missense	Exon 8 of 12	ENSP00000633723.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446908 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719258

African (AFR) AF: 0.00 AC: 0 AN: 32428

American (AMR) AF: 0.00 AC: 0 AN: 40606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.00 AC: 0 AN: 82230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107998

Other (OTH) AF: 0.00 AC: 0 AN: 59748

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.068
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.29		Loss of ubiquitination at K206 (P = 0)
MVP		0.56
MPC		0.19
ClinPred		0.90	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.10
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -1

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

Other links and lift over

dbSNP: rs764685617; hg19: chr4-4436582;