5-71649202-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_022132.5(MCCC2):c.1322T>C(p.Ile441Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,614,198 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 5 hom. )

Consequence

MCCC2
NM_022132.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 8.02

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

3-methylcrotonyl-CoA carboxylase 2 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
3-methylcrotonyl-CoA carboxylase deficiency
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

MCCC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_022132.5

BP4

Computational evidence support a benign effect (MetaRNN=0.107370645).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022132.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC2	NM_022132.5	MANE Select	c.1322T>C	p.Ile441Thr	missense	Exon 14 of 17	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.1208T>C	p.Ile403Thr	missense	Exon 13 of 16	NP_001350076.1	Q9HCC0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCCC2	ENST00000340941.11	TSL:1 MANE Select	c.1322T>C	p.Ile441Thr	missense	Exon 14 of 17	ENSP00000343657.6	Q9HCC0-1
MCCC2	ENST00000682876.1		c.1451T>C	p.Ile484Thr	missense	Exon 15 of 18	ENSP00000508389.1	A0A804HLJ9
MCCC2	ENST00000888940.1		c.1349T>C	p.Ile450Thr	missense	Exon 14 of 17	ENSP00000558999.1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

211

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000998

AC:

251

AN:

251474

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00137

AC:

2000

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

996

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33480

American (AMR)

AF:

0.00203

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.000661

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00155

AC:

1728

AN:

1111962

Other (OTH)

AF:

0.00154

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

102

203

305

406

508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00138

AC:

211

AN:

152358

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000841

AC:

AN:

41596

American (AMR)

AF:

0.00333

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00166

AC:

113

AN:

68038

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000889

AC:

108

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-methylcrotonyl-CoA carboxylase 2 deficiency (5)

MCCC2-related disorder (1)

Methylcrotonyl-CoA carboxylase deficiency (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.11

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

1.0

PhyloP100

8.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Benign

0.11

Polyphen

0.98

Vest4

0.84

MVP

0.85

MPC

0.56

ClinPred

0.055

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.68

gMVP

0.89

Mutation Taster

=65/35

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over