chr12-109139711-C-A

Position:

chr12-109139711-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001093.4(ACACB):c.306C>A(p.Asn102Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,613,958 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

ACACB
NM_001093.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.547

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06689039).

BP6

Variant 12-109139711-C-A is Benign according to our data. Variant chr12-109139711-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1130119.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACACB	NM_001093.4 link	c.306C>A	p.Asn102Lys	missense_variant	2/53	ENST00000338432.12	NP_001084.3	O00763-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ACACB	ENST00000338432.12 link	c.306C>A	p.Asn102Lys	missense_variant	2/53	1	NM_001093.4	ENSP00000341044.7	O00763-1
ACACB	ENST00000377848.7 link	c.306C>A	p.Asn102Lys	missense_variant	1/52	1		ENSP00000367079.3	O00763-1
ACACB	ENST00000539864.1 link	c.231C>A	p.Asn77Lys	missense_variant	2/2	3		ENSP00000443494.1	F5H5C3
ACACB	ENST00000377854 link	c.-3697C>A		5_prime_UTR_variant	1/47	5		ENSP00000367085.6	F8W8T8

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000183

AC:

AN:

251346

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.000396

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000351

AC:

513

AN:

1461806

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

253

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000450

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000237

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.306C>A (p.N102K) alteration is located in exon 1 (coding exon 1) of the ACACB gene. This alteration results from a C to A substitution at nucleotide position 306, causing the asparagine (N) at amino acid position 102 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.0

DANN

Benign

0.97

DEOGEN2

Benign

0.39

T;.;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.66

.;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

L;.;L

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

N;D;N

REVEL

Benign

0.098

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.047

D;D;D

Polyphen

0.012

B;.;B

Vest4

0.17

MutPred

0.29

Gain of catalytic residue at P99 (P = 0.0016);.;Gain of catalytic residue at P99 (P = 0.0016);

MVP

0.42

MPC

0.29

ClinPred

0.059

GERP RS

3.5

Varity_R

0.11

gMVP

0.13

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over