5-71652791-C-G

Variant names:

• chr5-71652791-C-G
• rs138725621
• NM_022132.5:c.1574+37C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022132.5(MCCC2):​c.1574+37C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,550,190 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 33)
  • Exomes 𝑓: 0.015 (213 hom.)
• Consequence: MCCC2 NM_022132.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.14
• Publications: 1 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=-0.88).
• BP6: Variant 5-71652791-C-G is Benign according to our data. Variant chr5-71652791-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1801/152338) while in subpopulation NFE AF = 0.016 (1090/68034). AF 95% confidence interval is 0.0152. There are 23 homozygotes in GnomAd4. There are 909 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.1574+37C>G		intron	N/A	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.1460+37C>G		intron	N/A	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.1574+37C>G		intron	N/A	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000682876.1		c.1703+37C>G		intron	N/A	ENSP00000508389.1	A0A804HLJ9
	MCCC2	ENST00000888940.1		c.1601+37C>G		intron	N/A	ENSP00000558999.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1803 AN: 152220 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00968

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0122 AC: 3068 AN: 250460 AF XY: 0.0117

Gnomad AFR exome AF: 0.00261

Gnomad AMR exome AF: 0.00737

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0341

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0147 AC: 20493 AN: 1397852 Hom.: 213 Cov.: 24 AF XY: 0.0142 AC XY: 9914 AN XY: 699424

African (AFR) AF: 0.00231 AC: 74 AN: 32102

American (AMR) AF: 0.00744 AC: 332 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 499 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39390

South Asian (SAS) AF: 0.000695 AC: 59 AN: 84900

European-Finnish (FIN) AF: 0.0309 AC: 1644 AN: 53272

Middle Eastern (MID) AF: 0.0246 AC: 137 AN: 5580

European-Non Finnish (NFE) AF: 0.0162 AC: 17085 AN: 1053994

Other (OTH) AF: 0.0114 AC: 663 AN: 58242

GnomAD4 genome AF: 0.0118 AC: 1801 AN: 152338 Hom.: 23 Cov.: 33 AF XY: 0.0122 AC XY: 909 AN XY: 74496

African (AFR) AF: 0.00200 AC: 83 AN: 41572

American (AMR) AF: 0.00967 AC: 148 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.0350 AC: 372 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0160 AC: 1090 AN: 68034

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.0126 Hom.: 3

Bravo AF: 0.00955

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.52
DANN	Benign	0.41
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs138725621; hg19: chr5-70948618;