14-75579019-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017791.3(FLVCR2):c.47T>C(p.Val16Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,644 control chromosomes in the GnomAD database, including 69,852 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (13615 hom., cov: 31)
  • Exomes 𝑓: 0.26 (56237 hom.)
• Consequence: FLVCR2 NM_017791.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.852

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4904954E-6).
• BP6: Variant 14-75579019-T-C is Benign according to our data. Variant chr14-75579019-T-C is described in ClinVar as [Benign]. Clinvar id is 95818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLVCR2	NM_017791.3	c.47T>C	p.Val16Ala	missense_variant	1/10	ENST00000238667.9
FLVCR2-AS1	NR_110552.1	n.570A>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLVCR2	ENST00000238667.9	c.47T>C	p.Val16Ala	missense_variant	1/10	1	NM_017791.3	P1
FLVCR2-AS1	ENST00000455232.1	n.570A>G		non_coding_transcript_exon_variant	1/3	1
FLVCR2-AS1	ENST00000693551.1	n.634A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56753 AN: 151716 Hom.: 13577 Cov.: 31

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.354

GnomAD3 exomes AF: 0.322 AC: 81012 AN: 251410 Hom.: 15588 AF XY: 0.313 AC XY: 42580 AN XY: 135908

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.369

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.573

Gnomad SAS exome AF: 0.394

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.257 AC: 375928 AN: 1461810 Hom.: 56237 Cov.: 39 AF XY: 0.259 AC XY: 188451 AN XY: 727202

Gnomad4 AFR exome AF: 0.687

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.277

Gnomad4 EAS exome AF: 0.575

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.287

GnomAD4 genome AF: 0.374 AC: 56851 AN: 151834 Hom.: 13615 Cov.: 31 AF XY: 0.374 AC XY: 27757 AN XY: 74194

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.555

Gnomad4 SAS AF: 0.395

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.357

Alfa AF: 0.259 Hom.: 14574

Bravo AF: 0.399

TwinsUK AF: 0.217 AC: 804

ALSPAC AF: 0.212 AC: 817

ESP6500AA AF: 0.663 AC: 2920

ESP6500EA AF: 0.225 AC: 1931

ExAC AF: 0.325 AC: 39478

Asia WGS AF: 0.431 AC: 1500 AN: 3478

EpiCase AF: 0.224

EpiControl AF: 0.228

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 03, 2013

- -

Posterior column ataxia-retinitis pigmentosa syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fowler syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.7
Dann	Benign	0.34
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000035	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.0060
Sift	Benign	1.0	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.32
ClinPred		0.000011	T
GERP RS		-2.6
Varity_R		0.021
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs2287015; hg19: chr14-76045362; COSMIC: COSV53162426; COSMIC: COSV53162426;