chr13-48233453-C-T

Variant names:

• chr13-48233453-C-T
• rs751333259
• NM_021999.5:c.93C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_021999.5(ITM2B):​c.93C>T​(p.Pro31Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). 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: 0.0000014 (0 hom.)
• Consequence: ITM2B NM_021999.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.555
• 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_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 13-48233453-C-T is Benign according to our data. Variant chr13-48233453-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1906312.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.555 with no splicing effect.

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.93C>T	p.Pro31Pro	synonymous	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.93C>T	p.Pro31Pro	synonymous	Exon 1 of 6	ENSP00000497221.1	Q9Y287-1
	ITM2B	ENST00000970638.1		c.93C>T	p.Pro31Pro	synonymous	Exon 1 of 7	ENSP00000640697.1
	ITM2B	ENST00000899433.1		c.93C>T	p.Pro31Pro	synonymous	Exon 1 of 6	ENSP00000569492.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 141512 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383618 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 683936

African (AFR) AF: 0.00 AC: 0 AN: 28622

American (AMR) AF: 0.0000292 AC: 1 AN: 34230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24280

East Asian (EAS) AF: 0.00 AC: 0 AN: 33134

South Asian (SAS) AF: 0.00 AC: 0 AN: 77246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074662

Other (OTH) AF: 0.00 AC: 0 AN: 57180

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.6
DANN	Benign	0.96
PhyloP100		-0.56
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6

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: rs751333259; hg19: chr13-48807589;