14-85622436-C-T

Variant names:

• chr14-85622436-C-T
• rs1342192331
• NM_013231.6:c.922C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013231.6(FLRT2):​c.922C>T​(p.Arg308Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FLRT2 NM_013231.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

Genes affected

FLRT2 (HGNC:3761): (fibronectin leucine rich transmembrane protein 2) This gene encodes a member of the fibronectin leucine rich transmembrane (FLRT) family of cell adhesion molecules, which regulate early embryonic vascular and neural development. The encoded type I transmembrane protein has an extracellular region consisting of an N-terminal leucine-rich repeat domain and a type 3 fibronectin domain, followed by a transmembrane domain and a short C-terminal cytoplasmic tail domain. It functions as both a homophilic cell adhesion molecule and a heterophilic chemorepellent through its interaction with members of the uncoordinated-5 receptor family. Proteolytic removal of the extracellular region controls the migration of neurons in the developing cortex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLRT2	NM_013231.6	c.922C>T	p.Arg308Trp	missense_variant	Exon 2 of 2	ENST00000330753.6	NP_037363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLRT2	ENST00000330753.6	c.922C>T	p.Arg308Trp	missense_variant	Exon 2 of 2	1	NM_013231.6	ENSP00000332879.4
FLRT2	ENST00000554746.1	c.922C>T	p.Arg308Trp	missense_variant	Exon 2 of 2	1		ENSP00000451050.1
FLRT2	ENST00000682132.1	c.922C>T	p.Arg308Trp	missense_variant	Exon 2 of 2			ENSP00000507088.1
FLRT2	ENST00000683129.1	c.922C>T	p.Arg308Trp	missense_variant	Exon 2 of 2			ENSP00000507815.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.922C>T (p.R308W) alteration is located in exon 2 (coding exon 1) of the FLRT2 gene. This alteration results from a C to T substitution at nucleotide position 922, causing the arginine (R) at amino acid position 308 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.56		Gain of catalytic residue at A307 (P = 0.0851);Gain of catalytic residue at A307 (P = 0.0851);
MVP		0.87
MPC		1.0
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.53
gMVP		0.81

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: rs1342192331; hg19: chr14-86088780;