NM_018052.5:c.2311G>T

Variant names:

• chr16-70687966-C-A
• rs761762197
• NM_018052.5:c.2311G>T

Variant summary

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

The NM_018052.5(VAC14):​c.2311G>T​(p.Gly771Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,680 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G771R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: VAC14 NM_018052.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.59
• 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: 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.2311G>T	p.Gly771Trp	missense	Exon 19 of 19	NP_060522.3
	VAC14	NM_001351157.2		c.1609G>T	p.Gly537Trp	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.2311G>T	p.Gly771Trp	missense	Exon 19 of 19	ENSP00000261776.5	Q08AM6-1
	VAC14	ENST00000568548.5	TSL:1	n.*2037G>T		non_coding_transcript_exon	Exon 18 of 18	ENSP00000454650.1	H3BN23
	VAC14	ENST00000568886.5	TSL:1	n.*936G>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000457809.1	H3BUU8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437680 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 712986

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32526

American (AMR) AF: 0.00 AC: 0 AN: 43034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 38060

South Asian (SAS) AF: 0.00 AC: 0 AN: 83484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4776

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098004

Other (OTH) AF: 0.0000169 AC: 1 AN: 59154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.35		Loss of disorder (P = 0.0329)
MVP		0.13
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.35
gMVP		0.41

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: rs761762197; hg19: chr16-70721869;