rs2232774

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016579.4(CD320):c.11G>C(p.Gly4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,587,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

CD320
NM_016579.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.122

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08819246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD320	NM_016579.4 linkuse as main transcript	c.11G>C	p.Gly4Ala	missense_variant	1/5	ENST00000301458.10
CD320	NM_001165895.2 linkuse as main transcript	c.11G>C	p.Gly4Ala	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD320	ENST00000301458.10 linkuse as main transcript	c.11G>C	p.Gly4Ala	missense_variant	1/5	1	NM_016579.4	P1	Q9NPF0-1

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000148

AC:

AN:

202596

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

112834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000617

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000277

Gnomad OTH exome

AF:

0.000571

GnomAD4 exome

AF:

0.000256

AC:

367

AN:

1435006

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

170

AN XY:

713416

show subpopulations

Gnomad4 AFR exome

AF:

0.000182

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000307

Gnomad4 OTH exome

AF:

0.000285

GnomAD4 genome

AF:

0.000190

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000226

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000762

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic acidemia due to transcobalamin receptor defect

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 20, 2023	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4 of the CD320 protein (p.Gly4Ala). This variant is present in population databases (rs2232774, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CD320-related conditions. ClinVar contains an entry for this variant (Variation ID: 566210). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.11G>C (p.G4A) alteration is located in exon 1 (coding exon 1) of the CD320 gene. This alteration results from a G to C substitution at nucleotide position 11, causing the glycine (G) at amino acid position 4 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.38

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.088

T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.14

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.29

.;B

Vest4

0.11

MVP

0.94

MPC

0.52

ClinPred

0.20

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.13

gMVP

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over