rs773473997

Variant names:

• chr22-30626483-G-A
• rs773473997
• NM_000355.4:c.1246G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000355.4(TCN2):​c.1246G>A​(p.Asp416Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TCN2 NM_000355.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.156
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058948934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.1246G>A	p.Asp416Asn	missense_variant	Exon 9 of 9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.1165G>A	p.Asp389Asn	missense_variant	Exon 9 of 9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.1246G>A	p.Asp416Asn	missense_variant	Exon 9 of 9	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251404 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Transcobalamin II deficiency Uncertain:1

Sep 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 416 of the TCN2 protein (p.Asp416Asn). This variant is present in population databases (rs773473997, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TCN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 570957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TCN2 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;T;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.059	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.80	N;.;.;.
PhyloP100		0.16
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N;.;N;N
REVEL	Benign	0.062
Sift	Benign	0.17	T;.;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.14	B;.;B;.
Vest4		0.13
MutPred		0.33		Gain of ubiquitination at K415 (P = 0.1184);.;.;.;
MVP		0.21
MPC		0.012
ClinPred		0.076	T
GERP RS		-0.73
Varity_R		0.36
gMVP		0.58
Mutation Taster		=94/6	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: rs773473997; hg19: chr22-31022470;