19-8302540-G-A

Variant names:

• chr19-8302540-G-A
• rs146190802
• NM_016579.4:c.772C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258H) has been classified as Uncertain significance.

• 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
• Publications: 4 publications found

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]

CD320 Gene-Disease associations (from GenCC):

• methylmalonic acidemia due to transcobalamin receptor defect

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016579.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD320	NM_016579.4	MANE Select	c.772C>T	p.Arg258Cys	missense	Exon 5 of 5	NP_057663.1	Q9NPF0-1
	CD320	NM_001165895.2		c.646C>T	p.Arg216Cys	missense	Exon 4 of 4	NP_001159367.1	Q9NPF0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD320	ENST00000301458.10	TSL:1 MANE Select	c.772C>T	p.Arg258Cys	missense	Exon 5 of 5	ENSP00000301458.4	Q9NPF0-1
	CD320	ENST00000596002.5	TSL:1	n.*1060C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000471773.1	M0R1C4
	CD320	ENST00000596002.5	TSL:1	n.*1060C>T		3_prime_UTR	Exon 5 of 5	ENSP00000471773.1	M0R1C4

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

GnomAD2 exomes AF: 0.0188 AC: 4728 AN: 250996 AF XY: 0.0258

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 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

African (AFR) AF: 0.000299 AC: 10 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39682

South Asian (SAS) AF: 0.152 AC: 13085 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5766

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1111804

Other (OTH) AF: 0.00946 AC: 571 AN: 60388

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

African (AFR) AF: 0.000169 AC: 7 AN: 41540

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.173 AC: 831 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00214 Hom.: 41

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Methylmalonic acidemia due to transcobalamin receptor defect (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0019	T
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.29
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Benign	0.17	T
Sift4G	Benign	0.22	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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs146190802; hg19: chr19-8367424; COSMIC: COSV107378105; COSMIC: COSV107378105;