rs140806722

Variant names:

• chr5-71604443-T-A
• rs140806722
• NM_022132.5:c.599T>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I200V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (18 hom.)
• Consequence: MCCC2 NM_022132.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4 O:1
• Conservation: PhyloP100: 3.37
• Publications: 12 publications found

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

ACMG classification

Our verdict: Benign. The variant received -7 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=0.010521203).
• 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 VariationId is 167278.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.599T>A	p.Ile200Asn	missense	Exon 6 of 17	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.599T>A	p.Ile200Asn	missense	Exon 6 of 16	NP_001350076.1	Q9HCC0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC2	ENST00000340941.11	TSL:1 MANE Select	c.599T>A	p.Ile200Asn	missense	Exon 6 of 17	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000509358.7	TSL:1	c.599T>A	p.Ile200Asn	missense	Exon 6 of 12	ENSP00000420994.3	D6RDF7
	MCCC2	ENST00000629193.3	TSL:1	c.599T>A	p.Ile200Asn	missense	Exon 6 of 10	ENSP00000486535.2	A0A0D9SFE9

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152198 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00210 AC: 528 AN: 251438 AF XY: 0.00209

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 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.: 18 Cov.: 31 AF XY: 0.00374 AC XY: 2717 AN XY: 727200

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000824 AC: 44 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00494 AC: 5491 AN: 1111886

Other (OTH) AF: 0.00300 AC: 181 AN: 60396

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74478

African (AFR) AF: 0.000818 AC: 34 AN: 41578

American (AMR) AF: 0.00294 AC: 45 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00360 Hom.: 0

Bravo AF: 0.00238

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00197 AC: 239

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	3-methylcrotonyl-CoA carboxylase 2 deficiency (6)
-	3	1	not provided (4)
-	-	1	Methylcrotonyl-CoA carboxylase deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	-2.0	N
PhyloP100		3.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	4.4	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.43
MVP		0.58
MPC		0.19
ClinPred		0.011	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.75
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs140806722; hg19: chr5-70900270; COSMIC: COSV100040678; COSMIC: COSV100040678;