rs2336573

Positions:

chr19-8302825-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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 Benign. Variant got -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 id is 136684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8302825-C-T is described in Lovd as [Likely_benign]. Variant chr19-8302825-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
CD320	NM_016579.4 linkuse as main transcript	c.658G>A	p.Gly220Arg	missense_variant	4/5	ENST00000301458.10	NP_057663.1
CD320	NM_001165895.2 linkuse as main transcript	c.532G>A	p.Gly178Arg	missense_variant	3/4		NP_001159367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD320	ENST00000301458.10 linkuse as main transcript	c.658G>A	p.Gly220Arg	missense_variant	4/5	1	NM_016579.4	ENSP00000301458	P1	Q9NPF0-1
CD320	ENST00000596002.5 linkuse as main transcript	c.*946G>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	1		ENSP00000471773
CD320	ENST00000537716.6 linkuse as main transcript	c.532G>A	p.Gly178Arg	missense_variant	3/4	2		ENSP00000437697		Q9NPF0-2
CD320	ENST00000599573.1 linkuse as main transcript	c.*258G>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	2		ENSP00000471551

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

GnomAD3 exomes

AF:

0.0585

AC:

14701

AN:

251172

Hom.:

997

AF XY:

0.0532

AC XY:

7224

AN XY:

135818

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 SAS exome

AF:

0.0363

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

Gnomad4 AFR exome

AF:

0.311

Gnomad4 AMR exome

AF:

0.0480

Gnomad4 ASJ exome

AF:

0.0611

Gnomad4 EAS exome

AF:

0.0728

Gnomad4 SAS exome

AF:

0.0346

Gnomad4 FIN exome

AF:

0.0283

Gnomad4 NFE exome

AF:

0.0345

Gnomad4 OTH exome

AF:

0.0595

GnomAD4 genome

AF:

0.114

AC:

17381

AN:

152082

Hom.:

2030

Cov.:

AF XY:

0.113

AC XY:

8408

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.303

Gnomad4 AMR

AF:

0.0683

Gnomad4 ASJ

AF:

0.0580

Gnomad4 EAS

AF:

0.0884

Gnomad4 SAS

AF:

0.0396

Gnomad4 FIN

AF:

0.0297

Gnomad4 NFE

AF:

0.0348

Gnomad4 OTH

AF:

0.102

Alfa

AF:

0.0512

Hom.:

1084

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 26, 2013

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

MutationTaster

Benign

1.0

P;P

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

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