NM_001100164.2:c.107C>G

Variant names:

• chr6-143712076-C-G
• rs749125256
• NM_001100164.2:c.107C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP4

The NM_001100164.2(PHACTR2):​c.107C>G​(p.Thr36Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,597,742 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: PHACTR2 NM_001100164.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.87
• Publications: 0 publications found

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

ACMG classification

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

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, PROVEAN [when max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.33901575).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHACTR2	NM_001100164.2	MANE Select	c.107C>G	p.Thr36Arg	missense	Exon 2 of 13	NP_001093634.1	O75167-4
	PHACTR2	NM_014721.3		c.74C>G	p.Thr25Arg	missense	Exon 2 of 13	NP_055536.2	O75167-1
	PHACTR2	NM_001394736.1		c.278C>G	p.Thr93Arg	missense	Exon 2 of 12	NP_001381665.1	J3KP75

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHACTR2	ENST00000440869.7	TSL:2 MANE Select	c.107C>G	p.Thr36Arg	missense	Exon 2 of 13	ENSP00000417038.2	O75167-4
	PHACTR2	ENST00000427704.6	TSL:1	c.74C>G	p.Thr25Arg	missense	Exon 2 of 13	ENSP00000391763.2	O75167-1
	PHACTR2	ENST00000367582.7	TSL:1	c.107C>G	p.Thr36Arg	missense	Exon 2 of 12	ENSP00000356554.3	O75167-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000383 AC: 9 AN: 234992 AF XY: 0.0000548

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1445480 Hom.: 1 Cov.: 30 AF XY: 0.0000278 AC XY: 20 AN XY: 718704

African (AFR) AF: 0.00 AC: 0 AN: 32466

American (AMR) AF: 0.00 AC: 0 AN: 41004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25474

East Asian (EAS) AF: 0.00 AC: 0 AN: 39266

South Asian (SAS) AF: 0.000314 AC: 26 AN: 82830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106004

Other (OTH) AF: 0.0000168 AC: 1 AN: 59644

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41524

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000662 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.18		Loss of phosphorylation at T25 (P = 0.0292)
MVP		0.76
MPC		0.42
ClinPred		0.62	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.40
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs749125256; hg19: chr6-144033213; COSMIC: COSV105898806;