13-48233441-C-G

Variant names:

• chr13-48233441-C-G
• rs11556899
• NM_021999.5:c.81C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_021999.5(ITM2B):​c.81C>G​(p.Leu27Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L27L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ITM2B NM_021999.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.638
• 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=-0.53).
• BP7: Synonymous conserved (PhyloP=0.638 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.81C>G	p.Leu27Leu	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.81C>G	p.Leu27Leu	synonymous	Exon 1 of 6	ENSP00000497221.1	Q9Y287-1
	ITM2B	ENST00000970638.1		c.81C>G	p.Leu27Leu	synonymous	Exon 1 of 7	ENSP00000640697.1
	ITM2B	ENST00000899433.1		c.81C>G	p.Leu27Leu	synonymous	Exon 1 of 6	ENSP00000569492.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388528 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 686670

African (AFR) AF: 0.00 AC: 0 AN: 28778

American (AMR) AF: 0.00 AC: 0 AN: 34940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24338

East Asian (EAS) AF: 0.00 AC: 0 AN: 33510

South Asian (SAS) AF: 0.00 AC: 0 AN: 77572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077496

Other (OTH) AF: 0.00 AC: 0 AN: 57400

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.6
DANN	Benign	0.82
PhyloP100		0.64
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs11556899; hg19: chr13-48807577;