Genetic Variant CD320:p.Ala236Gly (chr19-8302605-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016579.4(CD320):c.707C>G(p.Ala236Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A236V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CD320
NM_016579.4 missense, splice_region

Scores

Splicing: ADA: 0.00002856

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.24

Publications

0 publications found

Variant links:

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)

CD320 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09114301).

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.707C>G	p.Ala236Gly	missense splice_region	Exon 5 of 5	NP_057663.1	Q9NPF0-1
	CD320	NM_001165895.2		c.581C>G	p.Ala194Gly	missense splice_region	Exon 4 of 4	NP_001159367.1	Q9NPF0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD320	ENST00000301458.10	TSL:1 MANE Select	c.707C>G	p.Ala236Gly	missense splice_region	Exon 5 of 5	ENSP00000301458.4	Q9NPF0-1
CD320	ENST00000596002.5	TSL:1	n.*995C>G		splice_region non_coding_transcript_exon	Exon 5 of 5	ENSP00000471773.1	M0R1C4
CD320	ENST00000596002.5	TSL:1	n.*995C>G		3_prime_UTR	Exon 5 of 5	ENSP00000471773.1	M0R1C4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249660

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.058

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.031

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.56

M_CAP

Benign

0.022

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.63

PhyloP100

-1.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.17

REVEL

Benign

0.16

Sift

Benign

0.61

Sift4G

Benign

0.39

Polyphen

0.0010

Vest4

0.13

MutPred

0.33

Gain of loop (P = 0.0435)

MVP

0.73

MPC

0.11

ClinPred

0.012

GERP RS

-8.1

Varity_R

0.013

gMVP

0.33

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000029

dbscSNV1_RF

Benign

0.17

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over