chr22-30612914-C-G

Position:

• chr22-30612914-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000215838.8(TCN2):​c.299C>G​(p.Pro100Arg) 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. 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. P100L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCN2 ENST00000215838.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCN2	NM_000355.4	c.299C>G	p.Pro100Arg	missense_variant	3/9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.299C>G	p.Pro100Arg	missense_variant	3/9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.299C>G	p.Pro100Arg	missense_variant	3/9	1	NM_000355.4	ENSP00000215838	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.0	M;.;.;M
MutationTaster	Benign	0.66	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.66
MutPred		0.71		Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);
MVP		0.75
MPC		0.054
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.31
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752901101; hg19: chr22-31008901;