rs143029449

Variant names:

• chr22-30607088-C-T
• rs143029449
• ENST00000883717.1:c.-244C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000450638.5(TCN2):​c.-420C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00969 in 601,064 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (9 hom., cov: 30)
  • Exomes 𝑓: 0.011 (74 hom.)
• Consequence: TCN2 ENST00000450638.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.808
• 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]

PES1 (HGNC:8848): (pescadillo ribosomal biogenesis factor 1) This gene encodes a nuclear protein that contains a breast cancer associated gene 1 (BRCA1) C-terminal interaction domain. The encoded protein interacts with BOP1 and WDR12 to form the PeBoW complex, which plays a critical role in cell proliferation via pre-rRNA processing and 60S ribosomal subunit maturation. Expression of this gene may play an important role in breast cancer proliferation and tumorigenicity. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Pseudogenes of this gene are located on the long arm of chromosome 4 and the short arm of chromosome 9. [provided by RefSeq, Aug 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 22-30607088-C-T is Benign according to our data. Variant chr22-30607088-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00722 (1100/152276) while in subpopulation SAS AF = 0.027 (130/4822). AF 95% confidence interval is 0.0232. There are 9 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000450638.5. 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.-244C>T		upstream_gene	N/A	NP_000346.2
	PES1	NM_001282327.1		c.-997G>A		upstream_gene	N/A	NP_001269256.1	F6VXF5
	PES1	NM_001282328.1		c.-1044G>A		upstream_gene	N/A	NP_001269257.1	B3KTZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	ENST00000883717.1		c.-244C>T		5_prime_UTR	Exon 1 of 9	ENSP00000553776.1
	TCN2	ENST00000450638.5	TSL:3	c.-420C>T		5_prime_UTR	Exon 1 of 10	ENSP00000394184.2	F8WE86
	TCN2	ENST00000423350.1	TSL:2	n.86C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1098 AN: 152160 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.0105 AC: 4726 AN: 448788 Hom.: 74 Cov.: 5 AF XY: 0.0119 AC XY: 2805 AN XY: 236684

African (AFR) AF: 0.00242 AC: 31 AN: 12790

American (AMR) AF: 0.00399 AC: 84 AN: 21072

Ashkenazi Jewish (ASJ) AF: 0.00343 AC: 46 AN: 13416

East Asian (EAS) AF: 0.000103 AC: 3 AN: 29230

South Asian (SAS) AF: 0.0316 AC: 1507 AN: 47734

European-Finnish (FIN) AF: 0.00475 AC: 125 AN: 26304

Middle Eastern (MID) AF: 0.0303 AC: 58 AN: 1914

European-Non Finnish (NFE) AF: 0.00973 AC: 2639 AN: 271130

Other (OTH) AF: 0.00925 AC: 233 AN: 25198

GnomAD4 genome AF: 0.00722 AC: 1100 AN: 152276 Hom.: 9 Cov.: 30 AF XY: 0.00717 AC XY: 534 AN XY: 74440

African (AFR) AF: 0.00176 AC: 73 AN: 41554

American (AMR) AF: 0.00405 AC: 62 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4822

European-Finnish (FIN) AF: 0.00527 AC: 56 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 699 AN: 68008

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00907 Hom.: 0

Bravo AF: 0.00655

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Transcobalamin II deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.2
DANN	Benign	0.77
PhyloP100		-0.81
PromoterAI		-0.076	Neutral
Mutation Taster		=300/0	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: rs143029449; hg19: chr22-31003075;