14-75579161-CT-C

Position:

• chr14-75579161-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017791.3(FLVCR2):​c.191delT​(p.Leu64fs) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLVCR2 NM_017791.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.216

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-75579161-CT-C is Pathogenic according to our data. Variant chr14-75579161-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3341082.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLVCR2	NM_017791.3	c.191delT	p.Leu64fs	frameshift_variant	1/10	ENST00000238667.9	NP_060261.2
FLVCR2-AS1	NR_110552.1	n.427delA		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLVCR2	ENST00000238667.9	c.191delT	p.Leu64fs	frameshift_variant	1/10	1	NM_017791.3	ENSP00000238667.4
FLVCR2-AS1	ENST00000455232.1	n.427delA		non_coding_transcript_exon_variant	1/3	1
FLVCR2-AS1	ENST00000693551.1	n.491delA		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fowler syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Faculty of Engineering and Natural Sciences, Biruni University

Apr 20, 2023

The NM_017791.3 c.191del, is a frameshift variant in FLVCR2 which is predicted to result in a premature stop codon at position 78, and likely results in an absent or disrupted protein product (PVS1). It was absent from large population studies(gnomAD)(PM2). The phenotypic features observed in the proband, including hydrocephalus and epilepsy attacks, are consistent with Fowler Syndrome, which has previously been associated with an autosomal recessive inheritance pattern in the FLVCR2 gene (PMID: 25677735). In the same proband, c.1021-7T>G change in the same gene was also detected. It is thought that these two variants together cause Fowler Syndrome by forming compound heterozygote. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr14-76045504;