Genetic Variant NM_001100164.2:c.62A>G (chr6-143712031-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001100164.2(PHACTR2):c.62A>G(p.Lys21Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,439,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. K21I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PHACTR2
NM_001100164.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.37

Publications

0 publications found

Variant links:

Genes affected

PHACTR2 (HGNC:20956): (phosphatase and actin regulator 2) Predicted to enable actin binding activity. Predicted to be involved in actin cytoskeleton organization. Predicted to be located in plasma membrane and platelet alpha granule membrane. Implicated in Parkinson's disease and multiple sclerosis. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

PHACTR2 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

PHACTR2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1271283).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100164.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHACTR2	NM_001100164.2	MANE Select	c.62A>G	p.Lys21Arg	missense	Exon 2 of 13	NP_001093634.1	O75167-4
PHACTR2	NM_014721.3		c.29A>G	p.Lys10Arg	missense	Exon 2 of 13	NP_055536.2	O75167-1
PHACTR2	NM_001394736.1		c.233A>G	p.Lys78Arg	missense	Exon 2 of 12	NP_001381665.1	J3KP75

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHACTR2	ENST00000440869.7	TSL:2 MANE Select	c.62A>G	p.Lys21Arg	missense	Exon 2 of 13	ENSP00000417038.2	O75167-4
PHACTR2	ENST00000427704.6	TSL:1	c.29A>G	p.Lys10Arg	missense	Exon 2 of 13	ENSP00000391763.2	O75167-1
PHACTR2	ENST00000367582.7	TSL:1	c.62A>G	p.Lys21Arg	missense	Exon 2 of 12	ENSP00000356554.3	O75167-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1439214

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

715026

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32074

American (AMR)

AF:

0.00

AC:

AN:

40360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24930

East Asian (EAS)

AF:

0.00

AC:

AN:

39220

South Asian (SAS)

AF:

0.00

AC:

AN:

81924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103040

Other (OTH)

AF:

0.00

AC:

AN:

59282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

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

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0069

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.0097

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0080

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

6.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.75

REVEL

Benign

0.039

Sift

Benign

0.27

Sift4G

Benign

0.35

Polyphen

0.015

Vest4

0.18

MutPred

0.14

Loss of ubiquitination at K10 (P = 8e-04)

MVP

0.51

MPC

0.058

ClinPred

0.89

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.17

gMVP

0.25

Mutation Taster

=74/26

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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