20-34882857-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_018677.4(ACSS2):c.242G>A(p.Arg81Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R81W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: ACSS2 NM_018677.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.97

Genes affected

ACSS2 (HGNC:15814): (acyl-CoA synthetase short chain family member 2) This gene encodes a cytosolic enzyme that catalyzes the activation of acetate for use in lipid synthesis and energy generation. The protein acts as a monomer and produces acetyl-CoA from acetate in a reaction that requires ATP. Expression of this gene is regulated by sterol regulatory element-binding proteins, transcription factors that activate genes required for the synthesis of cholesterol and unsaturated fatty acids. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07270014).
• BP6: Variant 20-34882857-G-A is Benign according to our data. Variant chr20-34882857-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2399709.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSS2	NM_018677.4	c.242G>A	p.Arg81Gln	missense_variant	2/18	ENST00000360596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSS2	ENST00000360596.7	c.242G>A	p.Arg81Gln	missense_variant	2/18	1	NM_018677.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250830 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000287 AC: 42 AN: 1461418 Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Benign	0.42
DEOGEN2	Benign	0.011	T;T;.;T;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T;T;D;D;D;D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.073	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.89	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.86	N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.73	T;T;T;T;T;T
Sift4G	Benign	0.82	T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;.
Vest4		0.073, 0.074
MutPred		0.40		.;Loss of methylation at R81 (P = 0.0499);.;Loss of methylation at R81 (P = 0.0499);Loss of methylation at R81 (P = 0.0499);Loss of methylation at R81 (P = 0.0499);
MVP		0.32
MPC		0.21
ClinPred		0.16	T
GERP RS		4.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.026
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs57031852; hg19: chr20-33470660;