rs6861176

Variant names:

• chr5-71632096-C-T
• rs6861176
• NM_022132.5:c.739-25C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-71632096-C-T
• chr5-71632096-C-G

Variant summary

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

The NM_022132.5(MCCC2):​c.739-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,611,572 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (61 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (56 hom.)
• Consequence: MCCC2 NM_022132.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.491
• Publications: 3 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=-0.77).
• BP6: Variant 5-71632096-C-T is Benign according to our data. Variant chr5-71632096-C-T is described in ClinVar as Benign. ClinVar VariationId is 261561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 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.739-25C>T		intron	N/A	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.625-25C>T		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.739-25C>T		intron	N/A	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000509358.7	TSL:1	c.739-25C>T		intron	N/A	ENSP00000420994.3	D6RDF7
	MCCC2	ENST00000629193.3	TSL:1	c.625-25C>T		intron	N/A	ENSP00000486535.2	A0A0D9SFE9

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2286 AN: 152180 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00385 AC: 969 AN: 251488 AF XY: 0.00284

Gnomad AFR exome AF: 0.0544

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00148 AC: 2160 AN: 1459274 Hom.: 56 Cov.: 31 AF XY: 0.00128 AC XY: 927 AN XY: 726192

African (AFR) AF: 0.0544 AC: 1817 AN: 33414

American (AMR) AF: 0.00237 AC: 106 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5754

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1109660

Other (OTH) AF: 0.00317 AC: 191 AN: 60318

GnomAD4 genome AF: 0.0151 AC: 2298 AN: 152298 Hom.: 61 Cov.: 33 AF XY: 0.0144 AC XY: 1070 AN XY: 74470

African (AFR) AF: 0.0532 AC: 2211 AN: 41550

American (AMR) AF: 0.00386 AC: 59 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00722 Hom.: 4

Bravo AF: 0.0170

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.8
DANN	Benign	0.77
PhyloP100		0.49
PromoterAI		0.012	Neutral
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: rs6861176; hg19: chr5-70927923;