13-48233441-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_021999.5(ITM2B):​c.81C>T​(p.Leu27Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,540,578 control chromosomes in the GnomAD database, including 825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (250 hom., cov: 31)
  • Exomes 𝑓: 0.011 (575 hom.)
• Consequence: ITM2B NM_021999.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.638
• Publications: 3 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 13-48233441-C-T is Benign according to our data. Variant chr13-48233441-C-T is described in ClinVar as Benign. ClinVar VariationId is 1210019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.638 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

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>T	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>T	p.Leu27Leu	synonymous	Exon 1 of 6	ENSP00000497221.1	Q9Y287-1
	ITM2B	ENST00000970638.1		c.81C>T	p.Leu27Leu	synonymous	Exon 1 of 7	ENSP00000640697.1
	ITM2B	ENST00000899433.1		c.81C>T	p.Leu27Leu	synonymous	Exon 1 of 6	ENSP00000569492.1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5205 AN: 151992 Hom.: 246 Cov.: 31

Gnomad AFR AF: 0.0991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0613

Gnomad SAS AF: 0.0776

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.0203 AC: 2959 AN: 145564 AF XY: 0.0221

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00678

Gnomad ASJ exome AF: 0.000387

Gnomad EAS exome AF: 0.0652

Gnomad FIN exome AF: 0.000497

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0107 AC: 14904 AN: 1388478 Hom.: 575 Cov.: 30 AF XY: 0.0122 AC XY: 8358 AN XY: 686650

African (AFR) AF: 0.104 AC: 2989 AN: 28770

American (AMR) AF: 0.00741 AC: 259 AN: 34938

Ashkenazi Jewish (ASJ) AF: 0.000329 AC: 8 AN: 24338

East Asian (EAS) AF: 0.0725 AC: 2430 AN: 33500

South Asian (SAS) AF: 0.0680 AC: 5277 AN: 77560

European-Finnish (FIN) AF: 0.000491 AC: 24 AN: 48868

Middle Eastern (MID) AF: 0.0107 AC: 60 AN: 5626

European-Non Finnish (NFE) AF: 0.00260 AC: 2798 AN: 1077482

Other (OTH) AF: 0.0185 AC: 1059 AN: 57396

GnomAD4 genome AF: 0.0344 AC: 5232 AN: 152100 Hom.: 250 Cov.: 31 AF XY: 0.0343 AC XY: 2553 AN XY: 74374

African (AFR) AF: 0.0993 AC: 4119 AN: 41492

American (AMR) AF: 0.0135 AC: 207 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0615 AC: 317 AN: 5154

South Asian (SAS) AF: 0.0775 AC: 374 AN: 4826

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10594

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 67960

Other (OTH) AF: 0.0323 AC: 68 AN: 2108

Alfa AF: 0.0175 Hom.: 82

Bravo AF: 0.0373

Asia WGS AF: 0.122 AC: 420 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.8
DANN	Benign	0.96
PhyloP100		0.64
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV66035864;