rs2232775

chr19-8308268-T-C

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.23A>G(p.Gln8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0656 in 1,582,434 control chromosomes in the GnomAD database, including 9,897 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (3924 hom., cov: 33)
  • Exomes 𝑓: 0.056 (5973 hom.)
• Consequence: CD320 NM_016579.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0190

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=3.4540892E-4).
• BP6: Variant 19-8308268-T-C is Benign according to our data. Variant chr19-8308268-T-C is described in ClinVar as [Benign]. Clinvar id is 136683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD320	NM_016579.4	c.23A>G	p.Gln8Arg	missense_variant	1/5	ENST00000301458.10
CD320	NM_001165895.2	c.23A>G	p.Gln8Arg	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD320	ENST00000301458.10	c.23A>G	p.Gln8Arg	missense_variant	1/5	1	NM_016579.4	P1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23211 AN: 152044 Hom.: 3903 Cov.: 33

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0785

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.0893

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.0825 AC: 16026 AN: 194160 Hom.: 1558 AF XY: 0.0843 AC XY: 9108 AN XY: 108078

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.0478

Gnomad ASJ exome AF: 0.0626

Gnomad EAS exome AF: 0.0854

Gnomad SAS exome AF: 0.183

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0331

Gnomad OTH exome AF: 0.0578

GnomAD4 exome AF: 0.0563 AC: 80467 AN: 1430272 Hom.: 5973 Cov.: 32 AF XY: 0.0589 AC XY: 41862 AN XY: 710656

Gnomad4 AFR exome AF: 0.431

Gnomad4 AMR exome AF: 0.0516

Gnomad4 ASJ exome AF: 0.0607

Gnomad4 EAS exome AF: 0.0719

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.0275

Gnomad4 NFE exome AF: 0.0346

Gnomad4 OTH exome AF: 0.0758

GnomAD4 genome AF: 0.153 AC: 23274 AN: 152162 Hom.: 3924 Cov.: 33 AF XY: 0.154 AC XY: 11428 AN XY: 74394

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.0784

Gnomad4 ASJ AF: 0.0580

Gnomad4 EAS AF: 0.0895

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.0297

Gnomad4 NFE AF: 0.0353

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0693 Hom.: 317

Bravo AF: 0.165

TwinsUK AF: 0.0378 AC: 140

ALSPAC AF: 0.0368 AC: 142

ESP6500AA AF: 0.309 AC: 1254

ESP6500EA AF: 0.0315 AC: 261

ExAC AF: 0.0787 AC: 9235

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 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

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	1.0
Dann	Benign	0.66
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.18	T;T
MetaRNN	Benign	0.00035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.029
MPC		0.12
ClinPred		0.0026	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.034
gMVP		0.75

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: rs2232775; hg19: chr19-8373152; COSMIC: COSV56845932; COSMIC: COSV56845932;