19-8302605-G-C

Variant names:

• chr19-8302605-G-C
• rs776727775
• NM_016579.4:c.707C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 18/23 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.

• 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

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09114301).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD320	NM_016579.4	c.707C>G	p.Ala236Gly	missense_variant, splice_region_variant	Exon 5 of 5	ENST00000301458.10	NP_057663.1
CD320	NM_001165895.2	c.581C>G	p.Ala194Gly	missense_variant, splice_region_variant	Exon 4 of 4		NP_001159367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD320	ENST00000301458.10	c.707C>G	p.Ala236Gly	missense_variant, splice_region_variant	Exon 5 of 5	1	NM_016579.4	ENSP00000301458.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249660 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134962

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.058
DANN	Benign	0.43
DEOGEN2	Benign	0.031	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.63	.;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.16
Sift	Benign	0.61	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0010	.;B
Vest4		0.13
MutPred		0.33		.;Gain of loop (P = 0.0435);
MVP		0.73
MPC		0.11
ClinPred		0.012	T
GERP RS		-8.1
Varity_R		0.013
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs776727775; hg19: chr19-8367489; COSMIC: COSV105013098; COSMIC: COSV105013098;