NM_018052.5:c.2289G>C

Variant names:

• chr16-70687988-C-G
• rs781773542
• NM_018052.5:c.2289G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_018052.5(VAC14):​c.2289G>C​(p.Leu763Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L763L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VAC14 NM_018052.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP7: Synonymous conserved (PhyloP=1.94 with no splicing effect.

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.2289G>C	p.Leu763Leu	synonymous	Exon 19 of 19	NP_060522.3
	VAC14	NM_001351157.2		c.1587G>C	p.Leu529Leu	synonymous	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.2289G>C	p.Leu763Leu	synonymous	Exon 19 of 19	ENSP00000261776.5	Q08AM6-1
	VAC14	ENST00000568548.5	TSL:1	n.*2015G>C		non_coding_transcript_exon	Exon 18 of 18	ENSP00000454650.1	H3BN23
	VAC14	ENST00000568886.5	TSL:1	n.*914G>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000457809.1	H3BUU8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449086 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 719668

African (AFR) AF: 0.00 AC: 0 AN: 32950

American (AMR) AF: 0.00 AC: 0 AN: 43844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 38810

South Asian (SAS) AF: 0.00 AC: 0 AN: 84758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5404

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1104420

Other (OTH) AF: 0.00 AC: 0 AN: 59736

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.8
DANN	Benign	0.80
PhyloP100		1.9

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: rs781773542; hg19: chr16-70721891;