13-48233446-TCC-T

Variant names:

• chr13-48233446-TCC-T
• rs746700992
• NM_021999.5:c.92_93delCC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_021999.5(ITM2B):​c.92_93delCC​(p.Pro31ArgfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,930 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ITM2B NM_021999.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 0 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: Likely_pathogenic. The variant received 6 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.
• PM2: Very rare variant in population databases, with high coverage

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.92_93delCC	p.Pro31ArgfsTer12	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.92_93delCC	p.Pro31ArgfsTer12	frameshift	Exon 1 of 6	ENSP00000497221.1	Q9Y287-1
	ITM2B	ENST00000970638.1		c.92_93delCC	p.Pro31ArgfsTer12	frameshift	Exon 1 of 7	ENSP00000640697.1
	ITM2B	ENST00000899433.1		c.92_93delCC	p.Pro31ArgfsTer12	frameshift	Exon 1 of 6	ENSP00000569492.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381930 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 683232

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

African (AFR) AF: 0.00 AC: 0 AN: 28546

American (AMR) AF: 0.00 AC: 0 AN: 34124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24142

East Asian (EAS) AF: 0.00 AC: 0 AN: 33020

South Asian (SAS) AF: 0.00 AC: 0 AN: 77028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1073808

Other (OTH) AF: 0.00 AC: 0 AN: 57068

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

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;