13-48233446-TCC-TC

Variant names:

• chr13-48233446-TC-T
• rs746700992
• NM_021999.5:c.93delC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_021999.5(ITM2B):​c.93delC​(p.Asp32ThrfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000876 in 1,380,718 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P31P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITM2B NM_021999.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 1 publications found

Genes affected

ITM2B (HGNC:6174): (integral membrane protein 2B) Amyloid precursor proteins are processed by beta-secretase and gamma-secretase to produce beta-amyloid peptides which form the characteristic plaques of Alzheimer disease. This gene encodes a transmembrane protein which is processed at the C-terminus by furin or furin-like proteases to produce a small secreted peptide which inhibits the deposition of beta-amyloid. Mutations which result in extension of the C-terminal end of the encoded protein, thereby increasing the size of the secreted peptide, are associated with two neurogenerative diseases, familial British dementia and familial Danish dementia. [provided by RefSeq, Oct 2009]

ITM2B Gene-Disease associations (from GenCC):

• ABri amyloidosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• ADan amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021999.5. 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
	ITM2B	NM_021999.5	MANE Select	c.93delC	p.Asp32ThrfsTer30	frameshift	Exon 1 of 6	NP_068839.1	Q9Y287-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITM2B	ENST00000647800.2	MANE Select	c.93delC	p.Asp32ThrfsTer30	frameshift	Exon 1 of 6	ENSP00000497221.1	Q9Y287-1
	ITM2B	ENST00000970638.1		c.93delC	p.Asp32ThrfsTer30	frameshift	Exon 1 of 7	ENSP00000640697.1
	ITM2B	ENST00000899433.1		c.93delC	p.Asp32ThrfsTer30	frameshift	Exon 1 of 6	ENSP00000569492.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150294 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.000667 AC: 91 AN: 136534 AF XY: 0.000655

Gnomad AFR exome AF: 0.000665

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000133

Gnomad EAS exome AF: 0.00137

Gnomad FIN exome AF: 0.000128

Gnomad NFE exome AF: 0.000813

Gnomad OTH exome AF: 0.000279

GnomAD4 exome AF: 0.0000876 AC: 121 AN: 1380718 Hom.: 0 Cov.: 30 AF XY: 0.0000908 AC XY: 62 AN XY: 682606

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

African (AFR) AF: 0.000175 AC: 5 AN: 28526

American (AMR) AF: 0.000647 AC: 22 AN: 34022

Ashkenazi Jewish (ASJ) AF: 0.000124 AC: 3 AN: 24118

East Asian (EAS) AF: 0.000303 AC: 10 AN: 32968

South Asian (SAS) AF: 0.0000910 AC: 7 AN: 76936

European-Finnish (FIN) AF: 0.0000412 AC: 2 AN: 48566

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5594

European-Non Finnish (NFE) AF: 0.0000624 AC: 67 AN: 1072962

Other (OTH) AF: 0.0000701 AC: 4 AN: 57026

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150294 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73342

African (AFR) AF: 0.00 AC: 0 AN: 40704

American (AMR) AF: 0.00 AC: 0 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67532

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00140 Hom.: 1

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=8/192	disease causing (fs/PTC)

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: rs746700992; hg19: chr13-48807582; COSMIC: COSV66034899;