NM_022132.5:c.1578A>G

Variant names:

• chr5-71656746-A-G
• rs114527907
• NM_022132.5:c.1578A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022132.5(MCCC2):​c.1578A>G​(p.Val526Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,612,588 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (30 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (18 hom.)
• Consequence: MCCC2 NM_022132.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.436
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-71656746-A-G is Benign according to our data. Variant chr5-71656746-A-G is described in ClinVar as Benign. ClinVar VariationId is 261558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.436 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00973 (1481/152226) while in subpopulation AFR AF = 0.0341 (1418/41528). AF 95% confidence interval is 0.0327. There are 30 homozygotes in GnomAd4. There are 688 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.1578A>G	p.Val526Val	synonymous	Exon 17 of 17	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.1464A>G	p.Val488Val	synonymous	Exon 16 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.1578A>G	p.Val526Val	synonymous	Exon 17 of 17	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000682876.1		c.1707A>G	p.Val569Val	synonymous	Exon 18 of 18	ENSP00000508389.1	A0A804HLJ9
	MCCC2	ENST00000888940.1		c.1605A>G	p.Val535Val	synonymous	Exon 17 of 17	ENSP00000558999.1

Frequencies

GnomAD3 genomes AF: 0.00972 AC: 1478 AN: 152108 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00237 AC: 595 AN: 251436 AF XY: 0.00180

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000913 AC: 1333 AN: 1460362 Hom.: 18 Cov.: 30 AF XY: 0.000801 AC XY: 582 AN XY: 726624

African (AFR) AF: 0.0337 AC: 1126 AN: 33424

American (AMR) AF: 0.00121 AC: 54 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1110686

Other (OTH) AF: 0.00164 AC: 99 AN: 60332

GnomAD4 genome AF: 0.00973 AC: 1481 AN: 152226 Hom.: 30 Cov.: 32 AF XY: 0.00924 AC XY: 688 AN XY: 74440

African (AFR) AF: 0.0341 AC: 1418 AN: 41528

American (AMR) AF: 0.00308 AC: 47 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00506 Hom.: 3

Bravo AF: 0.0110

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.1
DANN	Benign	0.71
PhyloP100		0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114527907; hg19: chr5-70952573;