rs16869487

Variant names:

• chr5-71645267-G-A
• rs16869487
• NM_022132.5:c.1150-944G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022132.5(MCCC2):​c.1150-944G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0947 in 152,098 control chromosomes in the GnomAD database, including 1,079 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.095 (1079 hom., cov: 32)
• Consequence: MCCC2 NM_022132.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.945
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC2	NM_022132.5	MANE Select	c.1150-944G>A		intron	N/A	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.1036-944G>A		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.1150-944G>A		intron	N/A	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000682876.1		c.1279-944G>A		intron	N/A	ENSP00000508389.1	A0A804HLJ9
	MCCC2	ENST00000888940.1		c.1150-944G>A		intron	N/A	ENSP00000558999.1

Frequencies

GnomAD3 genomes AF: 0.0945 AC: 14360 AN: 151980 Hom.: 1065 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.0859

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0681

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0947 AC: 14410 AN: 152098 Hom.: 1079 Cov.: 32 AF XY: 0.0952 AC XY: 7076 AN XY: 74358

African (AFR) AF: 0.202 AC: 8389 AN: 41470

American (AMR) AF: 0.0376 AC: 574 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3472

East Asian (EAS) AF: 0.0861 AC: 446 AN: 5182

South Asian (SAS) AF: 0.102 AC: 491 AN: 4820

European-Finnish (FIN) AF: 0.0858 AC: 907 AN: 10574

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0480 AC: 3265 AN: 67988

Other (OTH) AF: 0.0731 AC: 154 AN: 2108

Alfa AF: 0.0907 Hom.: 792

Bravo AF: 0.0951

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.94
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: rs16869487; hg19: chr5-70941094; COSMIC: COSV60157160; COSMIC: COSV60157160;