dbSNP rs2075260: ACACB:p.Val2141Ile (chr12-109259033-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001093.4(ACACB):c.6421G>A(p.Val2141Ile) variant causes a missense change. The variant allele was found at a frequency of 0.802 in 1,613,858 control chromosomes in the GnomAD database, including 520,681 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.78 ( 47107 hom., cov: 31)

Exomes 𝑓: 0.80 ( 473574 hom. )

Consequence

ACACB
NM_001093.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.14

Variant links:

Genes affected

ACACB (HGNC:85): (acetyl-CoA carboxylase beta) Acetyl-CoA carboxylase (ACC) is a complex multifunctional enzyme system. ACC is a biotin-containing enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ACC-beta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA transferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. [provided by RefSeq, Oct 2022]

ACACB links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.803952E-7).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACACB	NM_001093.4 link	c.6421G>A	p.Val2141Ile	missense_variant	Exon 47 of 53	ENST00000338432.12	NP_001084.3	O00763-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACACB	ENST00000338432.12 link	c.6421G>A	p.Val2141Ile	missense_variant	Exon 47 of 53	1	NM_001093.4	ENSP00000341044.7	O00763-1
ACACB	ENST00000377848.7 link	c.6421G>A	p.Val2141Ile	missense_variant	Exon 46 of 52	1		ENSP00000367079.3	O00763-1
ACACB	ENST00000377854.9 link	c.2419G>A	p.Val807Ile	missense_variant	Exon 46 of 47	5		ENSP00000367085.6	F8W8T8
ACACB	ENST00000538526.5 link	n.2419G>A		non_coding_transcript_exon_variant	Exon 19 of 26	5		ENSP00000443281.1	H0YGH5

Frequencies

GnomAD3 genomes

AF:

0.785

AC:

119286

AN:

151938

Hom.:

47088

Cov.:

show subpopulations

Gnomad AFR

AF:

0.710

Gnomad AMI

AF:

0.727

Gnomad AMR

AF:

0.846

Gnomad ASJ

AF:

0.839

Gnomad EAS

AF:

0.739

Gnomad SAS

AF:

0.660

Gnomad FIN

AF:

0.852

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.816

Gnomad OTH

AF:

0.796

GnomAD3 exomes

AF:

0.797

AC:

200465

AN:

251372

Hom.:

80552

AF XY:

0.792

AC XY:

107658

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.707

Gnomad AMR exome

AF:

0.883

Gnomad ASJ exome

AF:

0.822

Gnomad EAS exome

AF:

0.746

Gnomad SAS exome

AF:

0.669

Gnomad FIN exome

AF:

0.851

Gnomad NFE exome

AF:

0.814

Gnomad OTH exome

AF:

0.809

GnomAD4 exome

AF:

0.804

AC:

1174914

AN:

1461802

Hom.:

473574

Cov.:

AF XY:

0.800

AC XY:

581547

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.709

Gnomad4 AMR exome

AF:

0.879

Gnomad4 ASJ exome

AF:

0.822

Gnomad4 EAS exome

AF:

0.751

Gnomad4 SAS exome

AF:

0.673

Gnomad4 FIN exome

AF:

0.848

Gnomad4 NFE exome

AF:

0.814

Gnomad4 OTH exome

AF:

0.792

GnomAD4 genome

AF:

0.785

AC:

119353

AN:

152056

Hom.:

47107

Cov.:

AF XY:

0.786

AC XY:

58438

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.710

Gnomad4 AMR

AF:

0.846

Gnomad4 ASJ

AF:

0.839

Gnomad4 EAS

AF:

0.739

Gnomad4 SAS

AF:

0.657

Gnomad4 FIN

AF:

0.852

Gnomad4 NFE

AF:

0.816

Gnomad4 OTH

AF:

0.793

Alfa

AF:

0.803

Hom.:

52696

Bravo

AF:

0.784

TwinsUK

AF:

0.814

AC:

3020

ALSPAC

AF:

0.817

AC:

3147

ESP6500AA

AF:

0.711

AC:

3133

ESP6500EA

AF:

0.817

AC:

7025

ExAC

AF:

0.789

AC:

95791

Asia WGS

AF:

0.714

AC:

2484

AN:

3478

EpiCase

AF:

0.811

EpiControl

AF:

0.810

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.57

D;.;D

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.62

.;T;T

MetaRNN

Benign

6.8e-7

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-3.5

N;.;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.93

N;.;N

REVEL

Uncertain

0.39

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0020

B;.;B

Vest4

0.027

MPC

0.19

ClinPred

0.015

GERP RS

5.1

Varity_R

0.040

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over