2-149571135-G-C

Position:

• chr2-149571135-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015702.3(MMADHC):​c.646C>G​(p.Arg216Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,612,120 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: MMADHC NM_015702.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.40

Genes affected

MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0128771365).
• BP6: Variant 2-149571135-G-C is Benign according to our data. Variant chr2-149571135-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203837.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00176 (268/152286) while in subpopulation NFE AF= 0.00275 (187/68016). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.646C>G	p.Arg216Gly	missense_variant	7/8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.646C>G	p.Arg216Gly	missense_variant	7/8	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.748C>G	p.Arg250Gly	missense_variant	8/9	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.646C>G	p.Arg216Gly	missense_variant	6/7	2		ENSP00000389060.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 267 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00198 AC: 497 AN: 250912 Hom.: 3 AF XY: 0.00199 AC XY: 270 AN XY: 135628

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000459

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00161 AC: 2348 AN: 1459834 Hom.: 10 Cov.: 30 AF XY: 0.00167 AC XY: 1216 AN XY: 726248

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000430

Gnomad4 FIN exome AF: 0.00608

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74474

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00321 Hom.: 0

Bravo AF: 0.00113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00192 AC: 233

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2017	The R216G variant in the MMADHC gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R216G variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R216G variant is a non-conservative amino acid substitution, which occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R216G as a variant of unknown significance. This variant has been observed to be maternally inherited. -

MMADHC-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D;D
Eigen	Benign	0.024
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.31	B;B;P
Vest4		0.49
MVP		0.80
MPC		0.083
ClinPred		0.037	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141093638; hg19: chr2-150427649;