19-8302543-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016579.4(CD320):c.769G>A(p.Glu257Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,076 control chromosomes in the GnomAD database, including 82 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (45 hom.)
• Consequence: CD320 NM_016579.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.146

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=0.003944248).
• BP6: Variant 19-8302543-C-T is Benign according to our data. Variant chr19-8302543-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 382056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1827/152302) while in subpopulation AFR AF= 0.0409 (1698/41554). AF 95% confidence interval is 0.0392. There are 37 homozygotes in gnomad4. There are 885 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD320	NM_016579.4	c.769G>A	p.Glu257Lys	missense_variant	5/5	ENST00000301458.10
CD320	NM_001165895.2	c.643G>A	p.Glu215Lys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD320	ENST00000301458.10	c.769G>A	p.Glu257Lys	missense_variant	5/5	1	NM_016579.4	P1
CD320	ENST00000596002.5	c.*1057G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
CD320	ENST00000537716.6	c.643G>A	p.Glu215Lys	missense_variant	4/4	2
CD320	ENST00000599573.1	c.*369G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1824 AN: 152184 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00323 AC: 811 AN: 251092 Hom.: 19 AF XY: 0.00236 AC XY: 320 AN XY: 135762

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00150 AC: 2190 AN: 1461774 Hom.: 45 Cov.: 32 AF XY: 0.00136 AC XY: 989 AN XY: 727168

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.0120 AC: 1827 AN: 152302 Hom.: 37 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74464

Gnomad4 AFR AF: 0.0409

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00241 Hom.: 11

Bravo AF: 0.0141

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00361 AC: 438

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic acidemia due to transcobalamin receptor defect Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	11
Dann	Uncertain	0.99
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.13
Sift	Benign	0.034	D;T
Sift4G	Benign	0.14	T;T
Polyphen		0.063	.;B
Vest4		0.20
MVP		0.95
MPC		0.15
ClinPred		0.0030	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.49

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: rs2232786; hg19: chr19-8367427;