rs119103224

Positions:

• chr5-71649189-A-G
• chr5-71649189-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_022132.5(MCCC2):​c.1309A>G​(p.Ile437Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: MCCC2 NM_022132.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 7.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-71649189-A-G is Pathogenic according to our data. Variant chr5-71649189-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1925.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr5-71649189-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCCC2	NM_022132.5	c.1309A>G	p.Ile437Val	missense_variant	14/17	ENST00000340941.11
MCCC2	NM_001363147.1	c.1195A>G	p.Ile399Val	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCCC2	ENST00000340941.11	c.1309A>G	p.Ile437Val	missense_variant	14/17	1	NM_022132.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251480 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135914

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000381 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:3 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 11, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 437 of the MCCC2 protein (p.Ile437Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs119103224, gnomAD 0.005%). This missense change has been observed in individual(s) with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1925). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MCCC2 protein function. Studies have shown that this missense change results in activation of a cryptic donor site and introduces a premature termination codon (PMID: 11181649). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The MCCC2 c.1309A>G (p.Ile437Val) variant is described in two studies in which it is found in a compound heterozygous state in one individual and in a heterozygous state in another individual, both with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (Baumgartner et al. 2001; Grünert et al. 2012). The p.Ile437Val variant was not present in 100 controls (Grünert et al. 2012) and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies using RT-PCR showed that the p.Ile437Val variant activates a cryptic splice donor site, which when used results in the deletion of the last 64 base pairs of exon 14 from the mature transcript. Direct sequencing of the RT-PCR product showed that virtually all the transcript present uses the new donor site (Baumgartner et al. 2001). Based on the evidence, the p.Ile437Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2001	- -

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.94	N;N
REVEL	Pathogenic	0.74
Sift	Benign	0.049	D;T
Sift4G	Benign	0.11	T;T
Polyphen		0.29	B;.
Vest4		0.83
MVP		0.92
MPC		0.11
ClinPred		0.19	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.69		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs119103224; hg19: chr5-70945016;