22-30614444-G-C

Variant names:

• chr22-30614444-G-C
• NM_000355.4:c.523G>C
• TCN2 p.Val175Leu

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000355.4(TCN2):​c.523G>C​(p.Val175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 in silico tools predict a benign 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. V175M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCN2 NM_000355.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67
• Publications: 0 publications found

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]

TCN2 Gene-Disease associations (from GenCC):

• transcobalamin II deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000355.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	NM_000355.4	MANE Select	c.523G>C	p.Val175Leu	missense	Exon 4 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.442G>C	p.Val148Leu	missense	Exon 4 of 9	NP_001171655.1	P20062-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	ENST00000215838.8	TSL:1 MANE Select	c.523G>C	p.Val175Leu	missense	Exon 4 of 9	ENSP00000215838.3	P20062-1
	TCN2	ENST00000407817.3	TSL:1	c.442G>C	p.Val148Leu	missense	Exon 4 of 9	ENSP00000384914.3	P20062-2
	TCN2	ENST00000947107.1		c.523G>C	p.Val175Leu	missense	Exon 4 of 10	ENSP00000617166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.065	T
Varity_R		0.48
gMVP		0.62
Mutation Taster		=77/23	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-31010431;