20-34876769-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018677.4(ACSS2):c.124C>A(p.Pro42Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000792 in 1,413,066 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: ACSS2 NM_018677.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0630

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005499065).
• BP6: Variant 20-34876769-C-A is Benign according to our data. Variant chr20-34876769-C-A is described in ClinVar as [Benign]. Clinvar id is 781546.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000405 (511/1260782) while in subpopulation AFR AF= 0.017 (425/25032). AF 95% confidence interval is 0.0156. There are 4 homozygotes in gnomad4_exome. There are 231 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSS2	NM_018677.4	c.124C>A	p.Pro42Thr	missense_variant	1/18	ENST00000360596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSS2	ENST00000360596.7	c.124C>A	p.Pro42Thr	missense_variant	1/18	1	NM_018677.4	P4

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152166 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000410 AC: 23 AN: 56076 Hom.: 0 AF XY: 0.000340 AC XY: 11 AN XY: 32380

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.000499

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000405 AC: 511 AN: 1260782 Hom.: 4 Cov.: 31 AF XY: 0.000376 AC XY: 231 AN XY: 613894

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.000788

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000270

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000894

Gnomad4 OTH exome AF: 0.000801

GnomAD4 genome AF: 0.00399 AC: 608 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74474

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00416

ESP6500AA AF: 0.00429 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000541 AC: 28

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;T;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
MetaRNN	Benign	0.0055	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.035	N;.;.;.;N
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.47	T;D;D;T;T
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.0040	B;.;.;.;.
Vest4		0.12
MVP		0.22
MPC		1.8
ClinPred		0.011	T
GERP RS		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.16
gMVP		0.47

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: rs146486104; hg19: chr20-33464572;