dbSNP rs553169056: PHLDB2:p.Ala218Glu (chr3-111884730-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001134438.2(PHLDB2):c.653C>A(p.Ala218Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PHLDB2
NM_001134438.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0620

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056946695).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134438.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHLDB2	NM_001134438.2	MANE Select	c.653C>A	p.Ala218Glu	missense	Exon 2 of 18	NP_001127910.1	Q86SQ0-1
PHLDB2	NM_001134439.2		c.653C>A	p.Ala218Glu	missense	Exon 2 of 18	NP_001127911.1	Q86SQ0-1
PHLDB2	NM_001134437.2		c.734C>A	p.Ala245Glu	missense	Exon 3 of 18	NP_001127909.1	Q86SQ0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHLDB2	ENST00000431670.7	TSL:1 MANE Select	c.653C>A	p.Ala218Glu	missense	Exon 2 of 18	ENSP00000405405.2	Q86SQ0-1
PHLDB2	ENST00000393925.7	TSL:1	c.653C>A	p.Ala218Glu	missense	Exon 2 of 18	ENSP00000377502.3	Q86SQ0-1
PHLDB2	ENST00000481953.5	TSL:1	c.653C>A	p.Ala218Glu	missense	Exon 1 of 16	ENSP00000418319.1	Q86SQ0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.064

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0089

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.22

M_CAP

Benign

0.013

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

-0.062

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.51

REVEL

Benign

0.052

Sift

Benign

0.033

Sift4G

Uncertain

0.040

Polyphen

0.15

Vest4

0.27

MutPred

0.13

Gain of glycosylation at S216 (P = 0.0382)

MVP

0.30

MPC

0.11

ClinPred

0.087

GERP RS

-0.78

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.056

gMVP

0.24

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over