22-30615687-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000355.4(TCN2):ā€‹c.840T>Cā€‹(p.Asp280=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,230 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0074 ( 15 hom., cov: 33)
Exomes š‘“: 0.00098 ( 15 hom. )

Consequence

TCN2
NM_000355.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.26
Variant links:
Genes affected
TCN2 (HGNC:11653): (transcobalamin 2) This gene encodes a member of the vitamin B12-binding protein family. This family of proteins, alternatively referred to as R binders, is expressed in various tissues and secretions. This plasma protein binds cobalamin and mediates the transport of cobalamin into cells. This protein and other mammalian cobalamin-binding proteins, such as transcobalamin I and gastric intrisic factor, may have evolved by duplication of a common ancestral gene. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP6
Variant 22-30615687-T-C is Benign according to our data. Variant chr22-30615687-T-C is described in ClinVar as [Benign]. Clinvar id is 341203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30615687-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-4.26 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00737 (1123/152340) while in subpopulation AFR AF= 0.0248 (1032/41564). AF 95% confidence interval is 0.0236. There are 15 homozygotes in gnomad4. There are 520 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TCN2NM_000355.4 linkuse as main transcriptc.840T>C p.Asp280= synonymous_variant 6/9 ENST00000215838.8 NP_000346.2
TCN2NM_001184726.2 linkuse as main transcriptc.759T>C p.Asp253= synonymous_variant 6/9 NP_001171655.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TCN2ENST00000215838.8 linkuse as main transcriptc.840T>C p.Asp280= synonymous_variant 6/91 NM_000355.4 ENSP00000215838 P2P20062-1

Frequencies

GnomAD3 genomes
AF:
0.00738
AC:
1123
AN:
152222
Hom.:
15
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0249
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00308
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000382
Gnomad OTH
AF:
0.00764
GnomAD3 exomes
AF:
0.00227
AC:
572
AN:
251446
Hom.:
9
AF XY:
0.00168
AC XY:
228
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.0263
Gnomad AMR exome
AF:
0.00231
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.000323
Gnomad NFE exome
AF:
0.000343
Gnomad OTH exome
AF:
0.00277
GnomAD4 exome
AF:
0.000976
AC:
1427
AN:
1461890
Hom.:
15
Cov.:
35
AF XY:
0.000846
AC XY:
615
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0265
Gnomad4 AMR exome
AF:
0.00255
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000243
Gnomad4 NFE exome
AF:
0.000234
Gnomad4 OTH exome
AF:
0.00219
GnomAD4 genome
AF:
0.00737
AC:
1123
AN:
152340
Hom.:
15
Cov.:
33
AF XY:
0.00698
AC XY:
520
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0248
Gnomad4 AMR
AF:
0.00307
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000382
Gnomad4 OTH
AF:
0.00756
Alfa
AF:
0.00376
Hom.:
3
Bravo
AF:
0.00864
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000436
EpiControl
AF:
0.000771

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Transcobalamin II deficiency Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
CADD
Benign
0.020
DANN
Benign
0.25

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

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

Other links and lift over

dbSNP: rs79999752; hg19: chr22-31011674; API