rs2229384

Variant names:

• chr6-49457808-C-T
• rs2229384
• NM_000255.4:c.636G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000255.4(MMUT):​c.636G>A​(p.Lys212Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 1,611,684 control chromosomes in the GnomAD database, including 299,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26299 hom., cov: 32)
  • Exomes 𝑓: 0.61 (273682 hom.)
• Consequence: MMUT NM_000255.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.669
• Publications: 35 publications found

Genes affected

MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMUT Gene-Disease associations (from GenCC):

• methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• vitamin B12-unresponsive methylmalonic acidemia type mut-

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• vitamin B12-unresponsive methylmalonic acidemia type mut0

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 6-49457808-C-T is Benign according to our data. Variant chr6-49457808-C-T is described in ClinVar as Benign. ClinVar VariationId is 92687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.669 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000255.4. 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
	MMUT	NM_000255.4	MANE Select	c.636G>A	p.Lys212Lys	synonymous	Exon 3 of 13	NP_000246.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	ENST00000274813.4	TSL:1 MANE Select	c.636G>A	p.Lys212Lys	synonymous	Exon 3 of 13	ENSP00000274813.3
	MMUT	ENST00000878060.1		c.636G>A	p.Lys212Lys	synonymous	Exon 3 of 13	ENSP00000548119.1
	MMUT	ENST00000878062.1		c.636G>A	p.Lys212Lys	synonymous	Exon 3 of 13	ENSP00000548121.1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88723 AN: 151784 Hom.: 26275 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.562 AC: 140894 AN: 250846 AF XY: 0.572

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.545

Gnomad EAS exome AF: 0.485

Gnomad FIN exome AF: 0.593

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.609 AC: 888298 AN: 1459782 Hom.: 273682 Cov.: 42 AF XY: 0.610 AC XY: 443301 AN XY: 726320

African (AFR) AF: 0.572 AC: 19126 AN: 33428

American (AMR) AF: 0.330 AC: 14739 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14354 AN: 26110

East Asian (EAS) AF: 0.458 AC: 18158 AN: 39664

South Asian (SAS) AF: 0.642 AC: 55358 AN: 86190

European-Finnish (FIN) AF: 0.599 AC: 31976 AN: 53390

Middle Eastern (MID) AF: 0.562 AC: 3240 AN: 5762

European-Non Finnish (NFE) AF: 0.626 AC: 695394 AN: 1110214

Other (OTH) AF: 0.596 AC: 35953 AN: 60320

GnomAD4 genome AF: 0.585 AC: 88790 AN: 151902 Hom.: 26299 Cov.: 32 AF XY: 0.580 AC XY: 43030 AN XY: 74234

African (AFR) AF: 0.576 AC: 23863 AN: 41394

American (AMR) AF: 0.433 AC: 6620 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 1955 AN: 3468

East Asian (EAS) AF: 0.478 AC: 2465 AN: 5154

South Asian (SAS) AF: 0.650 AC: 3130 AN: 4812

European-Finnish (FIN) AF: 0.604 AC: 6369 AN: 10542

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.625 AC: 42501 AN: 67948

Other (OTH) AF: 0.554 AC: 1169 AN: 2110

Alfa AF: 0.599 Hom.: 21746

Bravo AF: 0.564

Asia WGS AF: 0.555 AC: 1931 AN: 3478

EpiCase AF: 0.606

EpiControl AF: 0.599

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (4)
-	-	1	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.4
DANN	Benign	0.66
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2229384; hg19: chr6-49425521; COSMIC: COSV51272718;