Genetic Variant NM_001320586.2:c.279T>A (chr2-54135454-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001320586.2(ACYP2):c.279T>A(p.Ser93Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,607,950 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 55 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 37 hom. )

Consequence

ACYP2
NM_001320586.2 missense, splice_region

Scores

Splicing: ADA: 0.0002627

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.47

Publications

4 publications found

Variant links:

Genes affected

ACYP2 (HGNC:180): (acylphosphatase 2) Acylphosphatase can hydrolyze the phosphoenzyme intermediate of different membrane pumps, particularly the Ca2+/Mg2+-ATPase from sarcoplasmic reticulum of skeletal muscle. Two isoenzymes have been isolated, called muscle acylphosphatase and erythrocyte acylphosphatase on the basis of their tissue localization. This gene encodes the muscle-type isoform (MT). An increase of the MT isoform is associated with muscle differentiation. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ACYP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065383017).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (2068/152228) while in subpopulation AFR AF = 0.0476 (1976/41538). AF 95% confidence interval is 0.0458. There are 55 homozygotes in GnomAd4. There are 965 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACYP2	NM_001320586.2 link	c.279T>A	p.Ser93Arg	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000607452.6	NP_001307515.1	U3KQL2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACYP2	ENST00000607452.6 link	c.279T>A	p.Ser93Arg	missense_variant, splice_region_variant	Exon 5 of 7	2	NM_001320586.2	ENSP00000475986.1		U3KQL2
ACYP2	ENST00000394666.9 link	c.60T>A	p.Gly20Gly	splice_region_variant, synonymous_variant	Exon 2 of 4	1		ENSP00000378161.3		P14621

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2064

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0476

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.00342

AC:

846

AN:

247234

AF XY:

0.00263

show subpopulations

Gnomad AFR exome

AF:

0.0479

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00150

GnomAD4 exome

AF:

0.00136

AC:

1985

AN:

1455722

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

851

AN XY:

724280

show subpopulations

African (AFR)

AF:

0.0485

AC:

1607

AN:

33138

American (AMR)

AF:

0.00195

AC:

AN:

44036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.0000353

AC:

AN:

85010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52908

Middle Eastern (MID)

AF:

0.00209

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000848

AC:

AN:

1109036

Other (OTH)

AF:

0.00304

AC:

183

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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

AF:

0.0136

AC:

2068

AN:

152228

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

965

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0476

AC:

1976

AN:

41538

American (AMR)

AF:

0.00399

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68000

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

191

287

382

478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.0153

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0540

AC:

238

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00462

AC:

561

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.089

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0065

PhyloP100

1.5

Sift4G

Uncertain

0.0080

Vest4

0.30

MVP

0.63

GERP RS

0.19

gMVP

0.33

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00026

dbscSNV1_RF

Benign

0.048

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over