rs2336573

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016579.4(CD320):c.658G>A(p.Gly220Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 1,613,920 control chromosomes in the GnomAD database, including 4,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G220G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 2030 hom., cov: 32)

Exomes 𝑓: 0.044 ( 2796 hom. )

Consequence

CD320
NM_016579.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.237

Publications

54 publications found

Variant links:

Genes affected

CD320 (HGNC:16692): (CD320 molecule) This gene encodes the transcobalamin receptor that is expressed at the cell surface. It mediates the cellular uptake of transcobalamin bound cobalamin (vitamin B12), and is involved in B-cell proliferation and immunoglobulin secretion. Mutations in this gene are associated with methylmalonic aciduria. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2011]

CD320 Gene-Disease associations (from GenCC):

methylmalonic acidemia due to transcobalamin receptor defect
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, Laboratory for Molecular Medicine

CD320 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0048907995).

BP6

Variant 19-8302825-C-T is Benign according to our data. Variant chr19-8302825-C-T is described in ClinVar as Benign. ClinVar VariationId is 136684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD320	NM_016579.4 link	c.658G>A	p.Gly220Arg	missense_variant	Exon 4 of 5	ENST00000301458.10	NP_057663.1
CD320	NM_001165895.2 link	c.532G>A	p.Gly178Arg	missense_variant	Exon 3 of 4		NP_001159367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD320	ENST00000301458.10 link	c.658G>A	p.Gly220Arg	missense_variant	Exon 4 of 5	1	NM_016579.4	ENSP00000301458.4

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17351

AN:

151968

Hom.:

2022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.303

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0684

Gnomad ASJ

AF:

0.0580

Gnomad EAS

AF:

0.0882

Gnomad SAS

AF:

0.0398

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0348

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.0585

AC:

14701

AN:

251172

AF XY:

0.0532

show subpopulations

Gnomad AFR exome

AF:

0.308

Gnomad AMR exome

AF:

0.0456

Gnomad ASJ exome

AF:

0.0633

Gnomad EAS exome

AF:

0.0884

Gnomad FIN exome

AF:

0.0273

Gnomad NFE exome

AF:

0.0344

Gnomad OTH exome

AF:

0.0486

GnomAD4 exome

AF:

0.0437

AC:

63861

AN:

1461838

Hom.:

2796

Cov.:

AF XY:

0.0425

AC XY:

30872

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.311

AC:

10425

AN:

33472

American (AMR)

AF:

0.0480

AC:

2148

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0611

AC:

1597

AN:

26136

East Asian (EAS)

AF:

0.0728

AC:

2889

AN:

39698

South Asian (SAS)

AF:

0.0346

AC:

2985

AN:

86258

European-Finnish (FIN)

AF:

0.0283

AC:

1510

AN:

53418

Middle Eastern (MID)

AF:

0.0666

AC:

384

AN:

5768

European-Non Finnish (NFE)

AF:

0.0345

AC:

38332

AN:

1111968

Other (OTH)

AF:

0.0595

AC:

3591

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3562

7123

10685

14246

17808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1674

3348

5022

6696

8370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.114

AC:

17381

AN:

152082

Hom.:

2030

Cov.:

AF XY:

0.113

AC XY:

8408

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.303

AC:

12556

AN:

41440

American (AMR)

AF:

0.0683

AC:

1043

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0580

AC:

201

AN:

3466

East Asian (EAS)

AF:

0.0884

AC:

456

AN:

5156

South Asian (SAS)

AF:

0.0396

AC:

191

AN:

4826

European-Finnish (FIN)

AF:

0.0297

AC:

315

AN:

10616

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0348

AC:

2364

AN:

67990

Other (OTH)

AF:

0.102

AC:

214

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

684

1368

2051

2735

3419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0583

Hom.:

2846

Bravo

AF:

0.127

TwinsUK

AF:

0.0372

AC:

138

ALSPAC

AF:

0.0350

AC:

135

ESP6500AA

AF:

0.312

AC:

1374

ESP6500EA

AF:

0.0386

AC:

332

ExAC

AF:

0.0634

AC:

7691

Asia WGS

AF:

0.0820

AC:

286

AN:

3478

EpiCase

AF:

0.0425

EpiControl

AF:

0.0385

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 26, 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 acidemia due to transcobalamin receptor defect

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

8.6

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.10

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

.;L

PhyloP100

0.24

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.5

D;N

REVEL

Benign

0.23

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.27

.;B

Vest4

0.15

MutPred

0.073

.;Loss of catalytic residue at A219 (P = 0.0641);

MPC

0.15

ClinPred

0.014

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.60

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over