rs1131603

Positions:

• chr22-30622988-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000355.4(TCN2):​c.1127T>C​(p.Leu376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,614,044 control chromosomes in the GnomAD database, including 1,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (138 hom., cov: 31)
  • Exomes 𝑓: 0.044 (1618 hom.)
• Consequence: TCN2 NM_000355.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 2.93

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002260387).
• BP6: Variant 22-30622988-T-C is Benign according to our data. Variant chr22-30622988-T-C is described in ClinVar as [Benign]. Clinvar id is 341214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30622988-T-C is described in Lovd as [Benign]. Variant chr22-30622988-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0363 (5529/152192) while in subpopulation NFE AF= 0.0498 (3389/67996). AF 95% confidence interval is 0.0484. There are 138 homozygotes in gnomad4. There are 2713 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 138 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCN2	NM_000355.4	c.1127T>C	p.Leu376Ser	missense_variant	8/9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.1046T>C	p.Leu349Ser	missense_variant	8/9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.1127T>C	p.Leu376Ser	missense_variant	8/9	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5527 AN: 152074 Hom.: 137 Cov.: 31

Gnomad AFR AF: 0.00785

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0472

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0422 AC: 10609 AN: 251480 Hom.: 298 AF XY: 0.0426 AC XY: 5786 AN XY: 135914

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0200

Gnomad FIN exome AF: 0.0942

Gnomad NFE exome AF: 0.0553

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0444 AC: 64866 AN: 1461852 Hom.: 1618 Cov.: 31 AF XY: 0.0444 AC XY: 32302 AN XY: 727232

Gnomad4 AFR exome AF: 0.00633

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0444

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.0902

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0410

GnomAD4 genome AF: 0.0363 AC: 5529 AN: 152192 Hom.: 138 Cov.: 31 AF XY: 0.0365 AC XY: 2713 AN XY: 74392

Gnomad4 AFR AF: 0.00782

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0472

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0958

Gnomad4 NFE AF: 0.0498

Gnomad4 OTH AF: 0.0337

Alfa AF: 0.0477 Hom.: 420

Bravo AF: 0.0316

TwinsUK AF: 0.0442 AC: 164

ALSPAC AF: 0.0415 AC: 160

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0501 AC: 431

ExAC AF: 0.0427 AC: 5180

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0516

EpiControl AF: 0.0546

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	This variant is associated with the following publications: (PMID: 28334792, 23754956) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Transcobalamin II deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.66	T;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.69	N;.;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.013	D;.;D;T
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.22
MPC		0.055
ClinPred		0.0060	T
GERP RS		5.5
Varity_R		0.59
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs1131603; hg19: chr22-31018975;