Genetic Variant NM_001308172.2:c.179C>G (chr16-20465518-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001308172.2(ACSM2A):c.179C>G(p.Ala60Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A60T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACSM2A
NM_001308172.2 missense, splice_region

Scores

Splicing: ADA: 0.00005989

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.12

Publications

0 publications found

Variant links:

Genes affected

ACSM2A (HGNC:32017): (acyl-CoA synthetase medium chain family member 2A) This gene encodes a mitochondrial acyl-coenzyme A synthetase that is specific for medium chain fatty acids. These enzymes catalyze fatty acid activation, the first step of fatty acid metabolism, through the transfer of acyl-CoA. These enzymes also participate in the glycine conjugation pathway in the detoxification of xenobiotics such as benzoate and ibuprofen. Expression levels of this gene in the kidney may be correlated with kidney function. This gene and its paralog ACSM2B (Gene ID: 348158), both present on chromosome 16, likely arose from a chromosomal duplication event. [provided by RefSeq, May 2017]

ACSM2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057154775).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308172.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSM2A	NM_001308172.2	MANE Select	c.179C>G	p.Ala60Gly	missense splice_region	Exon 3 of 14	NP_001295101.1	Q08AH3
ACSM2A	NM_001308954.2		c.179C>G	p.Ala60Gly	missense splice_region	Exon 4 of 15	NP_001295883.1	Q08AH3
ACSM2A	NM_001308169.2		c.-59C>G		splice_region	Exon 2 of 13	NP_001295098.1	F5GWL3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSM2A	ENST00000573854.6	TSL:1 MANE Select	c.179C>G	p.Ala60Gly	missense splice_region	Exon 3 of 14	ENSP00000459451.1	Q08AH3
ACSM2A	ENST00000219054.10	TSL:1	c.179C>G	p.Ala60Gly	missense splice_region	Exon 4 of 15	ENSP00000219054.6	Q08AH3
ACSM2A	ENST00000396104.2	TSL:1	c.179C>G	p.Ala60Gly	missense splice_region	Exon 2 of 13	ENSP00000379411.2	Q08AH3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461556

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111764

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.9

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.065

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.11

M_CAP

Benign

0.0058

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.2

PhyloP100

-1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

REVEL

Benign

0.057

Sift

Benign

0.25

Sift4G

Benign

0.19

Polyphen

0.0080

Vest4

0.21

MutPred

0.32

Gain of ubiquitination at K59 (P = 0.0645)

MVP

0.061

MPC

0.31

ClinPred

0.39

GERP RS

-0.45

Varity_R

0.18

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000060

dbscSNV1_RF

Benign

0.018

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over