Genetic Variant ENSG00000250264:c.1933-5371_1933-5370insTTTTTTTTT (chr6-32822322-G-GAAAAAAAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The ENST00000452392.2(ENSG00000250264):c.1933-5371_1933-5370insTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000845 in 1,183,020 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ENSG00000250264
ENST00000452392.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.143

Publications

0 publications found

Variant links:

Genes affected

ENSG00000250264 (HGNC:):

ENSG00000250264 links:

TAP2 (HGNC:44): (transporter 2, ATP binding cassette subfamily B member) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. This gene is located 7 kb telomeric to gene family member ABCB2. The protein encoded by this gene is involved in antigen presentation. This protein forms a heterodimer with ABCB2 in order to transport peptides from the cytoplasm to the endoplasmic reticulum. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Alternative splicing of this gene produces products which differ in peptide selectivity and level of restoration of surface expression of MHC class I molecules. [provided by RefSeq, Feb 2014]

TAP2 Gene-Disease associations (from GenCC):

MHC class I deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

TAP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP2	NM_018833.3 link	c.1933-13_1933-5dupTTTTTTTTT		splice_region_variant, intron_variant	Intron 11 of 11		NP_061313.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
ENSG00000250264	ENST00000452392.2 link	c.1933-5371_1933-5370insTTTTTTTTT	intron_variant	Intron 11 of 14	2	ENSP00000391806.2
TAP2	ENST00000652259.1 link	c.1933-5_1933-4insTTTTTTTTT	splice_region_variant, intron_variant	Intron 11 of 11		ENSP00000498827.1
ENSG00000307274	ENST00000824890.1 link	n.79+1442_79+1443insAAAAAAAAA	intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143850

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.45e-7

AC:

AN:

1183020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

585480

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24504

American (AMR)

AF:

0.00

AC:

AN:

27782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21102

East Asian (EAS)

AF:

0.00

AC:

AN:

32694

South Asian (SAS)

AF:

0.00

AC:

AN:

65300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4716

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

916492

Other (OTH)

AF:

0.00

AC:

AN:

48462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

143850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69708

African (AFR)

AF:

0.00

AC:

AN:

39182

American (AMR)

AF:

0.00

AC:

AN:

14464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3358

East Asian (EAS)

AF:

0.00

AC:

AN:

5016

South Asian (SAS)

AF:

0.00

AC:

AN:

4600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65384

Other (OTH)

AF:

0.00

AC:

AN:

1976

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.14

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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6-32822322-GAA-GAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over