chr16-70688053-C-T

Variant names:

• chr16-70688053-C-T
• NM_018052.5:c.2224G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018052.5(VAC14):​c.2224G>A​(p.Asp742Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: VAC14 NM_018052.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.458
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0551185).

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.2224G>A	p.Asp742Asn	missense	Exon 19 of 19	NP_060522.3
	VAC14	NM_001351157.2		c.1522G>A	p.Asp508Asn	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.2224G>A	p.Asp742Asn	missense	Exon 19 of 19	ENSP00000261776.5	Q08AM6-1
	VAC14	ENST00000564512.1	TSL:1	n.502G>A		non_coding_transcript_exon	Exon 3 of 3
	VAC14	ENST00000568548.5	TSL:1	n.*1950G>A		non_coding_transcript_exon	Exon 18 of 18	ENSP00000454650.1	H3BN23

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.46
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.025
Sift	Benign	0.48	T
Sift4G	Benign	0.53	T
Polyphen		0.0030	B
Vest4		0.078
MutPred		0.21		Gain of catalytic residue at D742 (P = 0.0608)
MVP		0.043
MPC		0.42
ClinPred		0.12	T
GERP RS		3.1
Varity_R		0.063
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr16-70721956;