14-85622712-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013231.6(FLRT2):ā€‹c.1198C>Gā€‹(p.Pro400Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P400L) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000064 ( 0 hom. )

Consequence

FLRT2
NM_013231.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.39
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15199167).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FLRT2NM_013231.6 linkuse as main transcriptc.1198C>G p.Pro400Ala missense_variant 2/2 ENST00000330753.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FLRT2ENST00000330753.6 linkuse as main transcriptc.1198C>G p.Pro400Ala missense_variant 2/21 NM_013231.6 P1
FLRT2ENST00000554746.1 linkuse as main transcriptc.1198C>G p.Pro400Ala missense_variant 2/21 P1
FLRT2ENST00000682132.1 linkuse as main transcriptc.1198C>G p.Pro400Ala missense_variant 2/2 P1
FLRT2ENST00000683129.1 linkuse as main transcriptc.1198C>G p.Pro400Ala missense_variant 2/2 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251400
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000703
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000643
AC:
94
AN:
1461866
Hom.:
0
Cov.:
36
AF XY:
0.0000619
AC XY:
45
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000791
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000340

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 10, 2022The c.1198C>G (p.P400A) alteration is located in exon 2 (coding exon 1) of the FLRT2 gene. This alteration results from a C to G substitution at nucleotide position 1198, causing the proline (P) at amino acid position 400 to be replaced by an alanine (A). 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
Benign
0.062
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
14
DANN
Benign
0.46
DEOGEN2
Benign
0.043
T;T
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.024
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.76
.;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.34
N;N
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.45
N;N
REVEL
Benign
0.27
Sift
Benign
0.33
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.46
P;P
Vest4
0.27
MutPred
0.26
Loss of glycosylation at P400 (P = 0.0064);Loss of glycosylation at P400 (P = 0.0064);
MVP
0.39
MPC
0.29
ClinPred
0.11
T
GERP RS
6.2
Varity_R
0.068
gMVP
0.46

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1014385948; hg19: chr14-86089056; COSMIC: COSV58138028; COSMIC: COSV58138028; API