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5-71649248-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022132.5(MCCC2):ā€‹c.1368A>Gā€‹(p.Ala456=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.866 in 1,613,210 control chromosomes in the GnomAD database, including 606,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. A456A) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.83 ( 53183 hom., cov: 33)
Exomes š‘“: 0.87 ( 553816 hom. )

Consequence

MCCC2
NM_022132.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.20
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 5-71649248-A-G is Benign according to our data. Variant chr5-71649248-A-G is described in ClinVar as [Benign]. Clinvar id is 96029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71649248-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.2 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MCCC2NM_022132.5 linkuse as main transcriptc.1368A>G p.Ala456= synonymous_variant 14/17 ENST00000340941.11
MCCC2NM_001363147.1 linkuse as main transcriptc.1254A>G p.Ala418= synonymous_variant 13/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MCCC2ENST00000340941.11 linkuse as main transcriptc.1368A>G p.Ala456= synonymous_variant 14/171 NM_022132.5 P1Q9HCC0-1

Frequencies

GnomAD3 genomes
AF:
0.831
AC:
126472
AN:
152132
Hom.:
53140
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.704
Gnomad AMI
AF:
0.857
Gnomad AMR
AF:
0.875
Gnomad ASJ
AF:
0.908
Gnomad EAS
AF:
0.981
Gnomad SAS
AF:
0.935
Gnomad FIN
AF:
0.897
Gnomad MID
AF:
0.877
Gnomad NFE
AF:
0.865
Gnomad OTH
AF:
0.844
GnomAD3 exomes
AF:
0.884
AC:
222294
AN:
251442
Hom.:
98765
AF XY:
0.887
AC XY:
120522
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.700
Gnomad AMR exome
AF:
0.920
Gnomad ASJ exome
AF:
0.911
Gnomad EAS exome
AF:
0.986
Gnomad SAS exome
AF:
0.930
Gnomad FIN exome
AF:
0.895
Gnomad NFE exome
AF:
0.866
Gnomad OTH exome
AF:
0.884
GnomAD4 exome
AF:
0.870
AC:
1270710
AN:
1460960
Hom.:
553816
Cov.:
43
AF XY:
0.872
AC XY:
633850
AN XY:
726838
show subpopulations
Gnomad4 AFR exome
AF:
0.699
Gnomad4 AMR exome
AF:
0.914
Gnomad4 ASJ exome
AF:
0.914
Gnomad4 EAS exome
AF:
0.972
Gnomad4 SAS exome
AF:
0.926
Gnomad4 FIN exome
AF:
0.895
Gnomad4 NFE exome
AF:
0.863
Gnomad4 OTH exome
AF:
0.871
GnomAD4 genome
AF:
0.831
AC:
126576
AN:
152250
Hom.:
53183
Cov.:
33
AF XY:
0.836
AC XY:
62273
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.704
Gnomad4 AMR
AF:
0.876
Gnomad4 ASJ
AF:
0.908
Gnomad4 EAS
AF:
0.981
Gnomad4 SAS
AF:
0.936
Gnomad4 FIN
AF:
0.897
Gnomad4 NFE
AF:
0.865
Gnomad4 OTH
AF:
0.845
Alfa
AF:
0.857
Hom.:
70996
Bravo
AF:
0.824
Asia WGS
AF:
0.942
AC:
3274
AN:
3478
EpiCase
AF:
0.860
EpiControl
AF:
0.852

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 03, 2021- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 10, 2014- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
3-methylcrotonyl-CoA carboxylase 2 deficiency Benign:5
Benign, criteria provided, single submitterclinical testingPars Genome LabJun 19, 2021- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Nov 16, 2019- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.065
DANN
Benign
0.47
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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.

Other links and lift over

dbSNP: rs10064079; hg19: chr5-70945075; COSMIC: COSV60153659; API