NM_001100164.2:c.328A>G

Variant names:

• chr6-143753786-A-G
• rs768278021
• NM_001100164.2:c.328A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001100164.2(PHACTR2):​c.328A>G​(p.Asn110Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,450,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. N110S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PHACTR2 NM_001100164.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36907822).

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.328A>G	p.Asn110Asp	missense	Exon 4 of 13	NP_001093634.1	O75167-4
	PHACTR2	NM_014721.3		c.295A>G	p.Asn99Asp	missense	Exon 4 of 13	NP_055536.2	O75167-1
	PHACTR2	NM_001394736.1		c.499A>G	p.Asn167Asp	missense	Exon 4 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.328A>G	p.Asn110Asp	missense	Exon 4 of 13	ENSP00000417038.2	O75167-4
	PHACTR2	ENST00000427704.6	TSL:1	c.295A>G	p.Asn99Asp	missense	Exon 4 of 13	ENSP00000391763.2	O75167-1
	PHACTR2	ENST00000367582.7	TSL:1	c.328A>G	p.Asn110Asp	missense	Exon 4 of 12	ENSP00000356554.3	O75167-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 239230 AF XY: 0.0000231

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000175

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450840 Hom.: 0 Cov.: 29 AF XY: 0.00000416 AC XY: 3 AN XY: 721626

African (AFR) AF: 0.00 AC: 0 AN: 32786

American (AMR) AF: 0.00 AC: 0 AN: 41644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.0000762 AC: 3 AN: 39356

South Asian (SAS) AF: 0.00 AC: 0 AN: 83800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108728

Other (OTH) AF: 0.00 AC: 0 AN: 59856

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

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	Uncertain	0.51
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.0	L
PhyloP100		6.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.19		Loss of glycosylation at S98 (P = 0.0988)
MVP		0.78
MPC		0.41
ClinPred		0.92	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.32
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs768278021; hg19: chr6-144074923;