19-8302605-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_016579.4(CD320):​c.707C>T​(p.Ala236Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CD320
NM_016579.4 missense, splice_region

Scores

1
18
Splicing: ADA: 0.00005008
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.24
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.047570348).
BP6
Variant 19-8302605-G-A is Benign according to our data. Variant chr19-8302605-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2540723.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CD320NM_016579.4 linkuse as main transcriptc.707C>T p.Ala236Val missense_variant, splice_region_variant 5/5 ENST00000301458.10 NP_057663.1
CD320NM_001165895.2 linkuse as main transcriptc.581C>T p.Ala194Val missense_variant, splice_region_variant 4/4 NP_001159367.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CD320ENST00000301458.10 linkuse as main transcriptc.707C>T p.Ala236Val missense_variant, splice_region_variant 5/51 NM_016579.4 ENSP00000301458 P1Q9NPF0-1
CD320ENST00000596002.5 linkuse as main transcriptc.*995C>T splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant 5/51 ENSP00000471773
CD320ENST00000537716.6 linkuse as main transcriptc.581C>T p.Ala194Val missense_variant, splice_region_variant 4/42 ENSP00000437697 Q9NPF0-2
CD320ENST00000599573.1 linkuse as main transcriptc.*307C>T splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant 5/52 ENSP00000471551

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249660
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134962
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 SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461150
Hom.:
0
Cov.:
32
AF XY:
0.00000826
AC XY:
6
AN XY:
726770
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000371
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
0.15
DANN
Benign
0.68
DEOGEN2
Benign
0.040
.;T
Eigen
Benign
-1.9
Eigen_PC
Benign
-2.0
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.61
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.048
T;T
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Benign
0.55
.;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.5
N;N
REVEL
Benign
0.19
Sift
Benign
0.45
T;T
Sift4G
Benign
0.42
T;T
Polyphen
0.0030
.;B
Vest4
0.073
MVP
0.55
MPC
0.11
ClinPred
0.020
T
GERP RS
-8.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.012
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000050
dbscSNV1_RF
Benign
0.0080
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776727775; hg19: chr19-8367489; API