3-111884729-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001134438.2(PHLDB2):c.652G>T(p.Ala218Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A218V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

PHLDB2
NM_001134438.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.546

Variant links:

Genes affected

PHLDB2 (HGNC:29573): (pleckstrin homology like domain family B member 2) Enables cadherin binding activity. Involved in several processes, including negative regulation of focal adhesion assembly; regulation of cytoskeleton organization; and regulation of embryonic development. Located in several cellular components, including basal cortex; cell leading edge; and intermediate filament cytoskeleton. Colocalizes with focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

PHLDB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023870587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PHLDB2	NM_001134438.2 linkuse as main transcript	c.652G>T	p.Ala218Ser	missense_variant	2/18	ENST00000431670.7
PHLDB2	NM_001134439.2 linkuse as main transcript	c.652G>T	p.Ala218Ser	missense_variant	2/18
PHLDB2	NM_001134437.2 linkuse as main transcript	c.733G>T	p.Ala245Ser	missense_variant	3/18
PHLDB2	NM_145753.2 linkuse as main transcript	c.652G>T	p.Ala218Ser	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHLDB2	ENST00000431670.7 linkuse as main transcript	c.652G>T	p.Ala218Ser	missense_variant	2/18	1	NM_001134438.2	P3	Q86SQ0-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250834

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135548

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:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727238

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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 submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.652G>T (p.A218S) alteration is located in exon 2 (coding exon 1) of the PHLDB2 gene. This alteration results from a G to T substitution at nucleotide position 652, causing the alanine (A) at amino acid position 218 to be replaced by a serine (S). 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

0.064

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.69

Cadd

Benign

0.019

Dann

Benign

0.62

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.044

T;T;.;T;T;T;T;.

M_CAP

Benign

0.0088

MetaRNN

Benign

0.024

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.17

N;N;N;N;N;N;N;N

REVEL

Benign

0.020

Sift

Benign

0.36

T;T;T;T;T;T;T;T

Sift4G

Benign

0.94

T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;.;B;B;B;B

Vest4

0.13

MutPred

0.087

.;Gain of glycosylation at S216 (P = 0.0382);Gain of glycosylation at S216 (P = 0.0382);Gain of glycosylation at S216 (P = 0.0382);Gain of glycosylation at S216 (P = 0.0382);Gain of glycosylation at S216 (P = 0.0382);Gain of glycosylation at S216 (P = 0.0382);Gain of glycosylation at S216 (P = 0.0382);

MVP

0.21

MPC

0.083

ClinPred

0.065

GERP RS

0.34

Varity_R

0.033

gMVP

0.19

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over