dbSNP rs2267163: TCN2:c.754-31T>C (chr22-30615570-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000355.4(TCN2):c.754-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,238 control chromosomes in the GnomAD database, including 258,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.62 ( 29845 hom., cov: 32)

Exomes 𝑓: 0.56 ( 228923 hom. )

Consequence

TCN2
NM_000355.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.272

Publications

22 publications found

Variant links:

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: PanelApp Australia, ClinGen, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

TCN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 22-30615570-T-C is Benign according to our data. Variant chr22-30615570-T-C is described in ClinVar as Benign. ClinVar VariationId is 1236541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

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.754-31T>C		intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.673-31T>C		intron	N/A	NP_001171655.1	P20062-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TCN2	ENST00000215838.8	TSL:1 MANE Select	c.754-31T>C	intron	N/A	ENSP00000215838.3	P20062-1
TCN2	ENST00000407817.3	TSL:1	c.673-31T>C	intron	N/A	ENSP00000384914.3	P20062-2
TCN2	ENST00000947107.1		c.754-31T>C	intron	N/A	ENSP00000617166.1

Frequencies

GnomAD3 genomes

AF:

0.619

AC:

94080

AN:

151878

Hom.:

29815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.759

Gnomad AMI

AF:

0.575

Gnomad AMR

AF:

0.647

Gnomad ASJ

AF:

0.583

Gnomad EAS

AF:

0.441

Gnomad SAS

AF:

0.408

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.558

Gnomad OTH

AF:

0.604

GnomAD2 exomes

AF:

0.569

AC:

142218

AN:

249820

AF XY:

0.559

show subpopulations

Gnomad AFR exome

AF:

0.763

Gnomad AMR exome

AF:

0.667

Gnomad ASJ exome

AF:

0.591

Gnomad EAS exome

AF:

0.428

Gnomad FIN exome

AF:

0.635

Gnomad NFE exome

AF:

0.562

Gnomad OTH exome

AF:

0.578

GnomAD4 exome

AF:

0.556

AC:

811838

AN:

1461242

Hom.:

228923

Cov.:

AF XY:

0.551

AC XY:

400763

AN XY:

726854

show subpopulations

African (AFR)

AF:

0.779

AC:

26078

AN:

33464

American (AMR)

AF:

0.663

AC:

29634

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

15312

AN:

26124

East Asian (EAS)

AF:

0.445

AC:

17660

AN:

39690

South Asian (SAS)

AF:

0.419

AC:

36103

AN:

86240

European-Finnish (FIN)

AF:

0.635

AC:

33851

AN:

53312

Middle Eastern (MID)

AF:

0.547

AC:

3153

AN:

5768

European-Non Finnish (NFE)

AF:

0.554

AC:

615843

AN:

1111614

Other (OTH)

AF:

0.567

AC:

34204

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

20600

41201

61801

82402

103002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17288

34576

51864

69152

86440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.619

AC:

94161

AN:

151996

Hom.:

29845

Cov.:

AF XY:

0.618

AC XY:

45880

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.758

AC:

31467

AN:

41490

American (AMR)

AF:

0.647

AC:

9872

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.583

AC:

2023

AN:

3468

East Asian (EAS)

AF:

0.441

AC:

2275

AN:

5160

South Asian (SAS)

AF:

0.407

AC:

1964

AN:

4820

European-Finnish (FIN)

AF:

0.633

AC:

6681

AN:

10554

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.559

AC:

37948

AN:

67944

Other (OTH)

AF:

0.598

AC:

1255

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1785

3570

5356

7141

8926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

758

1516

2274

3032

3790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.585

Hom.:

38578

Bravo

AF:

0.628

Asia WGS

AF:

0.467

AC:

1627

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Transcobalamin II deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.0

(source)

DANN

Benign

0.70

PhyloP100

-0.27

BranchPoint Hunter

0.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over