NM_000355.4:c.17C>T

Variant names:

• chr22-30607348-C-T
• rs2145528950
• NM_000355.4:c.17C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000355.4(TCN2):​c.17C>T​(p.Ala6Val) 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 benign outcome for this variant. 15/22 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. A6D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCN2 NM_000355.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09193298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 9	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L
PhyloP100		-1.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.091
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.085
MutPred		0.68		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.38
MPC		0.0094
ClinPred		0.10	T
GERP RS		-0.020
PromoterAI		-0.040	Neutral
Varity_R		0.021
gMVP		0.26
Mutation Taster		=86/14	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

Other links and lift over

dbSNP: rs2145528950; hg19: chr22-31003335; COSMIC: COSV99308417; COSMIC: COSV99308417;