14-75579022-C-CG

Variant names:

• chr14-75579022-C-CG
• NM_017791.3:c.52dupG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017791.3(FLVCR2):​c.52dupG​(p.Glu18GlyfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLVCR2 NM_017791.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.698

Genes affected

FLVCR2 (HGNC:20105): (FLVCR choline and putative heme transporter 2) This gene encodes a member of the major facilitator superfamily. The encoded transmembrane protein is a calcium transporter. Unlike the related protein feline leukemia virus subgroup C receptor 1, the protein encoded by this locus does not bind to feline leukemia virus subgroup C envelope protein. The encoded protein may play a role in development of brain vascular endothelial cells, as mutations at this locus have been associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome. Alternatively spliced transcript variants have been described.[provided by RefSeq, Aug 2010]

FLVCR2-AS1 (HGNC:55854): (FLVCR2 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-75579022-C-CG is Pathogenic according to our data. Variant chr14-75579022-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3011058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLVCR2	NM_017791.3	c.52dupG	p.Glu18GlyfsTer52	frameshift_variant	Exon 1 of 10	ENST00000238667.9	NP_060261.2
FLVCR2-AS1	NR_110552.1	n.566dupC		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLVCR2	ENST00000238667.9	c.52dupG	p.Glu18GlyfsTer52	frameshift_variant	Exon 1 of 10	1	NM_017791.3	ENSP00000238667.4
FLVCR2-AS1	ENST00000455232.1	n.566dupC		non_coding_transcript_exon_variant	Exon 1 of 3	1
FLVCR2-AS1	ENST00000693551.1	n.630dupC		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Sep 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with FLVCR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu18Glyfs*52) in the FLVCR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLVCR2 are known to be pathogenic (PMID: 20206334, 20690116). -

Fowler syndrome Pathogenic:1

Oct 08, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant seems to be a novel variant, as it has not been previously reported in population databases or in the literature. However, several other truncating variants lying downstream of the variant, have been previously reported as likely pathogenic/pathogenic in the ClinVar database context of proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome. -

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-76045365;