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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.636G>A	p.Lys212Lys	synonymous_variant	Exon 3 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.636G>A	p.Lys212Lys	synonymous_variant	Exon 3 of 13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.636G>A	p.Lys212Lys	synonymous_variant	Exon 3 of 13	1	NM_000255.4	ENSP00000274813.3

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

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 57% of total chromosomes in ExAC -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 25, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;