2-54135454-T-G

Variant names:

• chr2-54135454-T-G
• rs13405053
• NM_138448.4:c.60T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001320586.2(ACYP2):​c.279T>G​(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 0.000000687 in 1,455,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACYP2 NM_001320586.2 missense, splice_region
• Scores: Splicing: ADA: 0.0001776
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

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]

ACMG classification

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=0.2383427).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320586.2. 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
	ACYP2	NM_138448.4	MANE Select	c.60T>G	p.Gly20Gly	splice_region synonymous	Exon 2 of 4	NP_612457.1	A0A140VJD7
	ACYP2	NM_001320586.2		c.279T>G	p.Ser93Arg	missense splice_region	Exon 5 of 7	NP_001307515.1	U3KQL2
	ACYP2	NM_001320587.2		c.186T>G	p.Ser62Arg	missense splice_region	Exon 4 of 6	NP_001307516.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACYP2	ENST00000394666.9	TSL:1 MANE Select	c.60T>G	p.Gly20Gly	splice_region synonymous	Exon 2 of 4	ENSP00000378161.3	P14621
	ACYP2	ENST00000406041.5	TSL:1	c.60T>G	p.Gly20Gly	splice_region synonymous	Exon 2 of 4	ENSP00000385674.2	E9PF46
	ACYP2	ENST00000607452.6	TSL:2	c.279T>G	p.Ser93Arg	missense splice_region	Exon 5 of 7	ENSP00000475986.1	U3KQL2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455772 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724304

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

African (AFR) AF: 0.00 AC: 0 AN: 33180

American (AMR) AF: 0.00 AC: 0 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109038

Other (OTH) AF: 0.00 AC: 0 AN: 60198

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.57
DEOGEN2	Benign	0.089	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.24	T
PhyloP100		1.5
Sift4G	Uncertain	0.0080	D
Vest4		0.30
MVP		0.63
GERP RS		0.19
gMVP		0.33
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.070		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: rs13405053; hg19: chr2-54362591;