16-70687980-C-A

Variant names:

• chr16-70687980-C-A
• rs145401972
• NM_018052.5:c.2297G>T

Variant summary

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

The NM_018052.5(VAC14):​c.2297G>T​(p.Arg766Leu) 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. R766Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: VAC14 NM_018052.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83
• Publications: 2 publications found

Genes affected

VAC14 (HGNC:25507): (VAC14 component of PIKFYVE complex) This gene encodes a scaffold protein that is a component of the PIKfyve protein kinase complex. This complex is responsible for the synthesis of phosphatidylinositol 3,5-bisphosphate, an important component of cellular membranes, from phosphatidylinositol 3-phosphate. Mice lacking a functional copy of this gene exhibit severe neurodegeneration. Mutations in the human gene have been identified in patients with a childhood onset progressive neurological disorder characterized by impaired movement, dystonia, and striatal abnormalities. [provided by RefSeq, May 2017]

VAC14 Gene-Disease associations (from GenCC):

• striatonigral degeneration, childhood-onset

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary neurological disease

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Yunis-Varon syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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_018052.5. 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
	VAC14	NM_018052.5	MANE Select	c.2297G>T	p.Arg766Leu	missense	Exon 19 of 19	NP_060522.3
	VAC14	NM_001351157.2		c.1595G>T	p.Arg532Leu	missense	Exon 18 of 18	NP_001338086.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAC14	ENST00000261776.10	TSL:1 MANE Select	c.2297G>T	p.Arg766Leu	missense	Exon 19 of 19	ENSP00000261776.5	Q08AM6-1
	VAC14	ENST00000568548.5	TSL:1	n.*2023G>T		non_coding_transcript_exon	Exon 18 of 18	ENSP00000454650.1	H3BN23
	VAC14	ENST00000568886.5	TSL:1	n.*922G>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000457809.1	H3BUU8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.55		Loss of MoRF binding (P = 0.0173)
MVP		0.38
MPC		0.62
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.53

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

Other links and lift over

dbSNP: rs145401972; hg19: chr16-70721883;