chr5-71587309-A-G

Variant names:

• chr5-71587309-A-G
• rs11746722
• ENST00000888940.1:c.-117A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000888940.1(MCCC2):​c.-117A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 1,445,368 control chromosomes in the GnomAD database, including 493,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47353 hom., cov: 33)
  • Exomes 𝑓: 0.83 (445733 hom.)
• Consequence: MCCC2 ENST00000888940.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0310
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-71587309-A-G is Benign according to our data. Variant chr5-71587309-A-G is described in ClinVar as Benign. ClinVar VariationId is 1175310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000888940.1. 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.-117A>G		upstream_gene	N/A	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.-117A>G		upstream_gene	N/A	NP_001350076.1	Q9HCC0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC2	ENST00000888940.1		c.-117A>G		5_prime_UTR	Exon 1 of 17	ENSP00000558999.1
	MCCC2	ENST00000682727.1		c.-117A>G		5_prime_UTR	Exon 1 of 17	ENSP00000507393.1	A0A804HJ84
	MCCC2	ENST00000888941.1		c.-117A>G		5_prime_UTR	Exon 1 of 17	ENSP00000559000.1

Frequencies

GnomAD3 genomes AF: 0.783 AC: 119131 AN: 152068 Hom.: 47331 Cov.: 33

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.822

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.814

GnomAD4 exome AF: 0.829 AC: 1072514 AN: 1293182 Hom.: 445733 Cov.: 23 AF XY: 0.830 AC XY: 522975 AN XY: 630114

African (AFR) AF: 0.629 AC: 17905 AN: 28470

American (AMR) AF: 0.887 AC: 22805 AN: 25722

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 18316 AN: 20356

East Asian (EAS) AF: 0.878 AC: 30161 AN: 34344

South Asian (SAS) AF: 0.826 AC: 55074 AN: 66672

European-Finnish (FIN) AF: 0.820 AC: 25505 AN: 31116

Middle Eastern (MID) AF: 0.851 AC: 3152 AN: 3704

European-Non Finnish (NFE) AF: 0.831 AC: 855024 AN: 1028990

Other (OTH) AF: 0.828 AC: 44572 AN: 53808

GnomAD4 genome AF: 0.783 AC: 119211 AN: 152186 Hom.: 47353 Cov.: 33 AF XY: 0.786 AC XY: 58479 AN XY: 74404

African (AFR) AF: 0.643 AC: 26681 AN: 41496

American (AMR) AF: 0.855 AC: 13085 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3089 AN: 3472

East Asian (EAS) AF: 0.880 AC: 4535 AN: 5156

South Asian (SAS) AF: 0.839 AC: 4053 AN: 4828

European-Finnish (FIN) AF: 0.808 AC: 8578 AN: 10612

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.831 AC: 56480 AN: 67996

Other (OTH) AF: 0.811 AC: 1712 AN: 2112

Alfa AF: 0.807 Hom.: 13694

Bravo AF: 0.782

Asia WGS AF: 0.826 AC: 2873 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.4
DANN	Benign	0.63
PhyloP100		-0.031
PromoterAI		0.0037	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs11746722; hg19: chr5-70883136;