22-30607363-T-C

Position:

• chr22-30607363-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000355.4(TCN2):​c.32T>C​(p.Leu11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TCN2 NM_000355.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCN2	NM_000355.4	c.32T>C	p.Leu11Pro	missense_variant	1/9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.32T>C	p.Leu11Pro	missense_variant	1/9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.32T>C	p.Leu11Pro	missense_variant	1/9	1	NM_000355.4	ENSP00000215838	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Transcobalamin II deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2104305). This variant has not been reported in the literature in individuals affected with TCN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 11 of the TCN2 protein (p.Leu11Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.46	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.0	M;.;M
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.022	D;D;D
Sift4G	Uncertain	0.040	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.75
MutPred		0.67		Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);
MVP		0.71
MPC		0.054
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.52
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-31003350;