rs277984

Variant names:

• chr5-71635139-A-G
• rs277984
• NM_022132.5:c.904-12A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-71635139-A-G
• chr5-71635139-A-C
• chr5-71635139-A-T

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.904-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,564 control chromosomes in the GnomAD database, including 107,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8664 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98805 hom.)
• Consequence: MCCC2 NM_022132.5 intron
• Scores: Splicing: ADA: 0.00006331
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.82
• Publications: 12 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=-0.92).
• BP6: Variant 5-71635139-A-G is Benign according to our data. Variant chr5-71635139-A-G is described in ClinVar as Benign. ClinVar VariationId is 96032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 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.904-12A>G		intron	N/A	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.790-12A>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.904-12A>G		intron	N/A	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000509358.7	TSL:1	c.904-12A>G		intron	N/A	ENSP00000420994.3	D6RDF7
	MCCC2	ENST00000629193.3	TSL:1	c.790-12A>G		intron	N/A	ENSP00000486535.2	A0A0D9SFE9

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47594 AN: 152014 Hom.: 8660 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.348

GnomAD2 exomes AF: 0.383 AC: 96393 AN: 251374 AF XY: 0.375

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.631

Gnomad ASJ exome AF: 0.450

Gnomad EAS exome AF: 0.526

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.391

GnomAD4 exome AF: 0.360 AC: 526268 AN: 1461432 Hom.: 98805 Cov.: 34 AF XY: 0.358 AC XY: 260286 AN XY: 727044

African (AFR) AF: 0.121 AC: 4058 AN: 33472

American (AMR) AF: 0.617 AC: 27601 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11968 AN: 26124

East Asian (EAS) AF: 0.529 AC: 21001 AN: 39680

South Asian (SAS) AF: 0.288 AC: 24869 AN: 86250

European-Finnish (FIN) AF: 0.300 AC: 16005 AN: 53410

Middle Eastern (MID) AF: 0.364 AC: 2101 AN: 5766

European-Non Finnish (NFE) AF: 0.357 AC: 396900 AN: 1111622

Other (OTH) AF: 0.360 AC: 21765 AN: 60386

GnomAD4 genome AF: 0.313 AC: 47603 AN: 152132 Hom.: 8664 Cov.: 32 AF XY: 0.314 AC XY: 23374 AN XY: 74356

African (AFR) AF: 0.137 AC: 5702 AN: 41538

American (AMR) AF: 0.506 AC: 7735 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1590 AN: 3466

East Asian (EAS) AF: 0.525 AC: 2715 AN: 5176

South Asian (SAS) AF: 0.301 AC: 1452 AN: 4822

European-Finnish (FIN) AF: 0.281 AC: 2969 AN: 10562

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24426 AN: 67976

Other (OTH) AF: 0.346 AC: 732 AN: 2114

Alfa AF: 0.347 Hom.: 3521

Bravo AF: 0.328

Asia WGS AF: 0.386 AC: 1340 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0010
DANN	Benign	0.44
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.050		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: rs277984; hg19: chr5-70930966; COSMIC: COSV60153597; COSMIC: COSV60153597;