rs2336573

Positions:

• chr19-8302825-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.237

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]

ACMG classification

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	c.658G>A	p.Gly220Arg	missense_variant	4/5	ENST00000301458.10	NP_057663.1
CD320	NM_001165895.2	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	c.658G>A	p.Gly220Arg	missense_variant	4/5	1	NM_016579.4	ENSP00000301458.4

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17351 AN: 151968 Hom.: 2022 Cov.: 32

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

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.: 34 AF XY: 0.0425 AC XY: 30872 AN XY: 727216

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.: 32 AF XY: 0.113 AC XY: 8408 AN XY: 74348

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

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	T
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	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs2336573; hg19: chr19-8367709; COSMIC: COSV56848201; COSMIC: COSV56848201;