19-8302539-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016579.4(CD320):c.773G>A(p.Arg258His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. R258C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: CD320 NM_016579.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0880

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03805688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD320	NM_016579.4	c.773G>A	p.Arg258His	missense_variant	5/5	ENST00000301458.10
CD320	NM_001165895.2	c.647G>A	p.Arg216His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD320	ENST00000301458.10	c.773G>A	p.Arg258His	missense_variant	5/5	1	NM_016579.4	P1
CD320	ENST00000596002.5	c.*1061G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
CD320	ENST00000537716.6	c.647G>A	p.Arg216His	missense_variant	4/4	2
CD320	ENST00000599573.1	c.*373G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 251036 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135730

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000975

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461522 Hom.: 0 Cov.: 32 AF XY: 0.0000605 AC XY: 44 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000994

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74452

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic acidemia due to transcobalamin receptor defect Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the CD320 protein (p.Arg258His). This variant is present in population databases (rs143156732, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 1439352). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	10
Dann	Benign	0.97
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.038	T;T
MetaSVM	Uncertain	-0.084	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.18
Sift	Benign	0.17	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.16	.;B
Vest4		0.12
MVP		0.86
MPC		0.15
ClinPred		0.017	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143156732; hg19: chr19-8367423;