5-71649248-A-G

Variant names:

• chr5-71649248-A-G
• rs10064079
• NM_022132.5:c.1368A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022132.5(MCCC2):​c.1368A>G​(p.Ala456Ala) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A456A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.83 (53183 hom., cov: 33)
  • Exomes 𝑓: 0.87 (553816 hom.)
• Consequence: MCCC2 NM_022132.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.20
• Publications: 24 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=-0.82).
• BP6: Variant 5-71649248-A-G is Benign according to our data. Variant chr5-71649248-A-G is described in ClinVar as Benign. ClinVar VariationId is 96029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC2	NM_022132.5	MANE Select	c.1368A>G	p.Ala456Ala	synonymous	Exon 14 of 17	NP_071415.1
	MCCC2	NM_001363147.1		c.1254A>G	p.Ala418Ala	synonymous	Exon 13 of 16	NP_001350076.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC2	ENST00000340941.11	TSL:1 MANE Select	c.1368A>G	p.Ala456Ala	synonymous	Exon 14 of 17	ENSP00000343657.6
	MCCC2	ENST00000682876.1		c.1497A>G	p.Ala499Ala	synonymous	Exon 15 of 18	ENSP00000508389.1
	MCCC2	ENST00000888940.1		c.1395A>G	p.Ala465Ala	synonymous	Exon 14 of 17	ENSP00000558999.1

Frequencies

GnomAD3 genomes AF: 0.831 AC: 126472 AN: 152132 Hom.: 53140 Cov.: 33

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

GnomAD2 exomes AF: 0.884 AC: 222294 AN: 251442 AF XY: 0.887

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 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

African (AFR) AF: 0.699 AC: 23378 AN: 33460

American (AMR) AF: 0.914 AC: 40870 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 23878 AN: 26128

East Asian (EAS) AF: 0.972 AC: 38583 AN: 39696

South Asian (SAS) AF: 0.926 AC: 79868 AN: 86238

European-Finnish (FIN) AF: 0.895 AC: 47802 AN: 53416

Middle Eastern (MID) AF: 0.878 AC: 5057 AN: 5762

European-Non Finnish (NFE) AF: 0.863 AC: 958711 AN: 1111164

Other (OTH) AF: 0.871 AC: 52563 AN: 60374

GnomAD4 genome AF: 0.831 AC: 126576 AN: 152250 Hom.: 53183 Cov.: 33 AF XY: 0.836 AC XY: 62273 AN XY: 74452

African (AFR) AF: 0.704 AC: 29239 AN: 41528

American (AMR) AF: 0.876 AC: 13401 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3153 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5084 AN: 5182

South Asian (SAS) AF: 0.936 AC: 4514 AN: 4824

European-Finnish (FIN) AF: 0.897 AC: 9515 AN: 10612

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58843 AN: 68006

Other (OTH) AF: 0.845 AC: 1789 AN: 2116

Alfa AF: 0.852 Hom.: 87413

Bravo AF: 0.824

Asia WGS AF: 0.942 AC: 3274 AN: 3478

EpiCase AF: 0.860

EpiControl AF: 0.852

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	3-methylcrotonyl-CoA carboxylase 2 deficiency (5)
-	-	5	not specified (5)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.065
DANN	Benign	0.47
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	disease causing (ClinVar)

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