19-8302540-G-A

Position:

• chr19-8302540-G-A

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.772C>T​(p.Arg258Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00912 in 1,613,784 control chromosomes in the GnomAD database, including 1,302 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 0.0056 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (1206 hom.)
• Consequence: CD320 NM_016579.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.290

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=0.0018918812).
• BP6: Variant 19-8302540-G-A is Benign according to our data. Variant chr19-8302540-G-A is described in ClinVar as [Benign]. Clinvar id is 377633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD320	NM_016579.4	c.772C>T	p.Arg258Cys	missense_variant	5/5	ENST00000301458.10	NP_057663.1
CD320	NM_001165895.2	c.646C>T	p.Arg216Cys	missense_variant	4/4		NP_001159367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD320	ENST00000301458.10	c.772C>T	p.Arg258Cys	missense_variant	5/5	1	NM_016579.4	ENSP00000301458	P1
CD320	ENST00000596002.5	c.*1060C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	1		ENSP00000471773
CD320	ENST00000537716.6	c.646C>T	p.Arg216Cys	missense_variant	4/4	2		ENSP00000437697
CD320	ENST00000599573.1	c.*372C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	2		ENSP00000471551

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 855 AN: 152160 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.0188 AC: 4728 AN: 250996 Hom.: 398 AF XY: 0.0258 AC XY: 3507 AN XY: 135726

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00131

Gnomad SAS exome AF: 0.151

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00949 AC: 13867 AN: 1461506 Hom.: 1206 Cov.: 33 AF XY: 0.0138 AC XY: 10004 AN XY: 727032

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.00946

GnomAD4 genome AF: 0.00563 AC: 857 AN: 152278 Hom.: 96 Cov.: 32 AF XY: 0.00853 AC XY: 635 AN XY: 74452

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000831 Hom.: 6

Bravo AF: 0.00122

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0213 AC: 2586

Asia WGS AF: 0.0760 AC: 262 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

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

Apr 19, 2016

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

Dec 22, 2023

- -

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	0.27
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.067	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Benign	1.3	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.17
Sift	Benign	0.17	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.078	.;B
Vest4		0.13
MPC		0.16
ClinPred		0.0060	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.31

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: rs146190802; hg19: chr19-8367424;