rs2270969

Variant names:

• chr3-183037179-A-G
• rs2270969
• NM_020166.5:c.1594+39T>C

Variant summary

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

The NM_020166.5(MCCC1):​c.1594+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 1,601,662 control chromosomes in the GnomAD database, including 2,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (542 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1874 hom.)
• Consequence: MCCC1 NM_020166.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.60
• Publications: 2 publications found

Genes affected

MCCC1 (HGNC:6936): (methylcrotonyl-CoA carboxylase subunit 1) This gene encodes the large 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. [provided by RefSeq, Jul 2008]

MCCC1 Gene-Disease associations (from GenCC):

• 3-methylcrotonyl-CoA carboxylase 1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 3-methylcrotonyl-CoA carboxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-183037179-A-G is Benign according to our data. Variant chr3-183037179-A-G is described in ClinVar as Benign. ClinVar VariationId is 261206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020166.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	NM_020166.5	MANE Select	c.1594+39T>C		intron	N/A	NP_064551.3
	MCCC1	NM_001363880.1		c.1267+39T>C		intron	N/A	NP_001350809.1
	MCCC1	NM_001293273.2		c.1243+39T>C		intron	N/A	NP_001280202.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	ENST00000265594.9	TSL:1 MANE Select	c.1594+39T>C		intron	N/A	ENSP00000265594.4
	MCCC1	ENST00000492597.5	TSL:1	c.1267+39T>C		intron	N/A	ENSP00000419898.1
	MCCC1	ENST00000497830.5	TSL:1	n.*1191+39T>C		intron	N/A	ENSP00000420088.1

Frequencies

GnomAD3 genomes AF: 0.0677 AC: 10289 AN: 151976 Hom.: 538 Cov.: 31

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0574

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0665

GnomAD2 exomes AF: 0.0622 AC: 15605 AN: 250792 AF XY: 0.0567

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.0886

Gnomad FIN exome AF: 0.0545

Gnomad NFE exome AF: 0.0277

Gnomad OTH exome AF: 0.0547

GnomAD4 exome AF: 0.0383 AC: 55563 AN: 1449568 Hom.: 1874 Cov.: 28 AF XY: 0.0380 AC XY: 27433 AN XY: 721776

African (AFR) AF: 0.124 AC: 4124 AN: 33166

American (AMR) AF: 0.144 AC: 6412 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 1114 AN: 26076

East Asian (EAS) AF: 0.121 AC: 4811 AN: 39642

South Asian (SAS) AF: 0.0540 AC: 4635 AN: 85882

European-Finnish (FIN) AF: 0.0552 AC: 2946 AN: 53410

Middle Eastern (MID) AF: 0.0440 AC: 189 AN: 4298

European-Non Finnish (NFE) AF: 0.0259 AC: 28552 AN: 1102528

Other (OTH) AF: 0.0464 AC: 2780 AN: 59892

GnomAD4 genome AF: 0.0678 AC: 10305 AN: 152094 Hom.: 542 Cov.: 31 AF XY: 0.0694 AC XY: 5159 AN XY: 74348

African (AFR) AF: 0.127 AC: 5244 AN: 41440

American (AMR) AF: 0.101 AC: 1548 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3470

East Asian (EAS) AF: 0.105 AC: 542 AN: 5160

South Asian (SAS) AF: 0.0568 AC: 274 AN: 4822

European-Finnish (FIN) AF: 0.0527 AC: 558 AN: 10592

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0273 AC: 1859 AN: 68010

Other (OTH) AF: 0.0668 AC: 141 AN: 2112

Alfa AF: 0.0424 Hom.: 911

Bravo AF: 0.0749

Asia WGS AF: 0.0990 AC: 345 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.65
PhyloP100		1.6
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: rs2270969; hg19: chr3-182754967;