rs119103226

chr5-71634977-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_022132.5(MCCC2):c.838G>T(p.Asp280Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MCCC2 NM_022132.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.93

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain CoA carboxyltransferase N-terminal (size 257) in uniprot entity MCCB_HUMAN there are 45 pathogenic changes around while only 2 benign (96%) in NM_022132.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 5-71634977-G-T is Pathogenic according to our data. Variant chr5-71634977-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCCC2	NM_022132.5	c.838G>T	p.Asp280Tyr	missense_variant	9/17	ENST00000340941.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCCC2	ENST00000340941.11	c.838G>T	p.Asp280Tyr	missense_variant	9/17	1	NM_022132.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 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: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251424 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000200 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 04, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 280 of the MCCC2 protein (p.Asp280Tyr). This variant is present in population databases (rs119103226, gnomAD 0.09%). This missense change has been observed in individuals with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 17968484, 22030835, 22150417, 28018443). ClinVar contains an entry for this variant (Variation ID: 1927). 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 expected to disrupt MCCC2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University	May 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.59	T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.94
MVP		1.0
MPC		0.58
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs119103226; hg19: chr5-70930804; COSMIC: COSV60154626;