rs140806722

Positions:

chr5-71604443-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_022132.5(MCCC2):c.599T>A(p.Ile200Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,614,066 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 18 hom. )

Consequence

MCCC2
NM_022132.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:3O:1

Conservation

PhyloP100: 3.37

Variant links:

Genes affected

MCCC2 (HGNC:6937): (methylcrotonyl-CoA carboxylase subunit 2) This gene encodes the small subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

MCCC2 links:

MCCC2 (HGNC:):

MCCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010521203).

BP6

Variant 5-71604443-T-A is Benign according to our data. Variant chr5-71604443-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8, not_provided=1}.

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCCC2	NM_022132.5 linkuse as main transcript	c.599T>A	p.Ile200Asn	missense_variant	6/17	ENST00000340941.11	NP_071415.1	Q9HCC0-1A0A140VK29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCCC2	ENST00000340941.11 linkuse as main transcript	c.599T>A	p.Ile200Asn	missense_variant	6/17	1	NM_022132.5	ENSP00000343657.6		Q9HCC0-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00210

AC:

528

AN:

251438

Hom.:

AF XY:

0.00209

AC XY:

284

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00384

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00399

AC:

5838

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

2717

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000824

Gnomad4 NFE exome

AF:

0.00494

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

AF:

0.00250

AC:

381

AN:

152316

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00360

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00197

AC:

239

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency

Uncertain:4Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	The MCCC2 c.599T>A; p.Ile200Asn variant (rs140806722) has been reported in two asymptomatic individuals who also harbored a frameshift variant in the other MCCC2 allele; clinical information was not provided for one of these individuals, but the other had elevated 3-hydroxyisovaleric acid and 3-hydroxyisovalerylcarnitine (Grünert 2012 and Shepard 2015). The variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variant ID: 167278), and is found in the non-Finnish European population with an overall allele frequency of 0.39% (495/126,690 alleles, including 2 homozygotes) in the Genome Aggregation Database. The isoleucine at codon 200 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ile200Asn variant is uncertain at this time. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for MCC2D, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:27601257). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2023	- -

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27601257, 34426522, 22642865, 25356967) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MCCC2: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 09, 2015	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 10, 2022

Variant summary: MCCC2 c.599T>A (p.Ile200Asn) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251438 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.0038 vs 0.0042), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. Nevertheless, c.599T>A has been reported in the literature in mothers who were identified with an elevated C5OH acylcarnitine level through their infant's newborn screening. These mothers were compound heterozygous with pathogenic variants but remained clinically asymptomatic (Grunert_2012, Shepard_2015, Fonseca_2016). These reports do not provide unequivocal conclusions about association of the variant with Methylcrotonyl-CoA Carboxylase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Methylcrotonyl-CoA carboxylase deficiency

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.29

T;D;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

-2.0

.;N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

4.4

.;N;N

REVEL

Benign

0.27

Sift

Benign

1.0

.;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.43

MVP

0.58

MPC

0.19

ClinPred

0.011

GERP RS

4.4

Varity_R

0.11

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

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

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