2-149575863-C-G

Variant names:

• chr2-149575863-C-G
• rs12232959
• NM_015702.3:c.479-22G>C

Variant summary

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

The NM_015702.3(MMADHC):​c.479-22G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,553,354 control chromosomes in the GnomAD database, including 458,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (35624 hom., cov: 33)
  • Exomes 𝑓: 0.77 (422844 hom.)
• Consequence: MMADHC NM_015702.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.14
• Publications: 8 publications found

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]

MMADHC Gene-Disease associations (from GenCC):

• inborn disorder of cobalamin metabolism and transport

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• methylmalonic aciduria and homocystinuria type cblD

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-149575863-C-G is Benign according to our data. Variant chr2-149575863-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.479-22G>C		intron_variant	Intron 5 of 7	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.479-22G>C		intron_variant	Intron 5 of 7	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.479-22G>C		intron_variant	Intron 5 of 8	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.479-22G>C		intron_variant	Intron 4 of 6	2		ENSP00000389060.1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98502 AN: 151850 Hom.: 35618 Cov.: 33

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.754

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.672

GnomAD2 exomes AF: 0.751 AC: 168708 AN: 224514 AF XY: 0.759

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.706

Gnomad ASJ exome AF: 0.811

Gnomad EAS exome AF: 0.858

Gnomad FIN exome AF: 0.850

Gnomad NFE exome AF: 0.783

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.772 AC: 1081754 AN: 1401388 Hom.: 422844 Cov.: 24 AF XY: 0.773 AC XY: 539225 AN XY: 697548

African (AFR) AF: 0.278 AC: 8981 AN: 32322

American (AMR) AF: 0.697 AC: 29287 AN: 42014

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 19982 AN: 24956

East Asian (EAS) AF: 0.873 AC: 34004 AN: 38958

South Asian (SAS) AF: 0.760 AC: 61973 AN: 81564

European-Finnish (FIN) AF: 0.847 AC: 44028 AN: 51978

Middle Eastern (MID) AF: 0.749 AC: 4170 AN: 5568

European-Non Finnish (NFE) AF: 0.784 AC: 835366 AN: 1065898

Other (OTH) AF: 0.756 AC: 43963 AN: 58130

GnomAD4 genome AF: 0.648 AC: 98521 AN: 151966 Hom.: 35624 Cov.: 33 AF XY: 0.653 AC XY: 48479 AN XY: 74274

African (AFR) AF: 0.302 AC: 12500 AN: 41368

American (AMR) AF: 0.658 AC: 10053 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2781 AN: 3470

East Asian (EAS) AF: 0.859 AC: 4432 AN: 5160

South Asian (SAS) AF: 0.767 AC: 3695 AN: 4818

European-Finnish (FIN) AF: 0.850 AC: 9008 AN: 10594

Middle Eastern (MID) AF: 0.728 AC: 211 AN: 290

European-Non Finnish (NFE) AF: 0.791 AC: 53734 AN: 67972

Other (OTH) AF: 0.673 AC: 1421 AN: 2112

Alfa AF: 0.709 Hom.: 5319

Bravo AF: 0.618

Asia WGS AF: 0.789 AC: 2711 AN: 3438

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Methylmalonic aciduria and homocystinuria type cblD Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.85
DANN	Benign	0.66
PhyloP100		-2.1
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: rs12232959; hg19: chr2-150432377; COSMIC: COSV57574667;