11-5225832-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000518.5(HBB):​c.316-106C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,168,954 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 pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

HBB
NM_000518.5 intron

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: -0.634
Variant links:
Genes affected
HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5225832-G-C is Pathogenic according to our data. Variant chr11-5225832-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225832-G-C is described in Lovd as [Pathogenic]. Variant chr11-5225832-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBBNM_000518.5 linkc.316-106C>G intron_variant Intron 2 of 2 ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.316-106C>G intron_variant Intron 2 of 2 1 NM_000518.5 ENSP00000333994.3 P68871
HBBENST00000647020.1 linkc.316-106C>G intron_variant Intron 2 of 2 ENSP00000494175.1 P68871
HBBENST00000475226.1 linkn.248-106C>G intron_variant Intron 1 of 1 2
HBBENST00000633227.1 linkn.*132-106C>G intron_variant Intron 2 of 2 3 ENSP00000488004.1 A0A0J9YWK4

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000266
AC:
27
AN:
1016752
Hom.:
0
AF XY:
0.0000305
AC XY:
16
AN XY:
524838
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000337
Gnomad4 OTH exome
AF:
0.0000438
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Nov 18, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HBB c.316-106C>G variant (rs34690599, HbVar ID: 891), also known as IVS-II-745 C>G, is reported in the heterozygous state in individuals with beta(+) thalassemia minor and in the homozygous and compound heterozygous state in individuals with transfusion-dependent beta-thalassemia major (Orkin 1982, Ropero 2013, HbVar database). Functional characterization of the variant indicates an accumulation of beta globin transcript containing intron 2 sequences (Orkin 1982). This variant is also reported in ClinVar (Variation ID: 15457). This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a cryptic donor splice site, consistent with the observed phenotype in functional studies. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Orkin S et al. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982; 296(5858):627-31. PMID: 6280057. Ropero P et al. Association in cis of the mutations +20 (C>T) in the 5' untranslated region and IVS-II-745 (C>G) on the beta-globin gene. Hemoglobin. 2013; 37(2):112-8. PMID: 23425204. -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

HBB: PM2, PP4:Moderate, PS4:Moderate, PP3 -

Mar 28, 2020
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 05, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 28, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 15, 2025
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 2375910, 28399358, 22975760, 19657842, 6280057, 23425204, 2200760, 25408857, 36882369, 32860008, 11559932, 2713503, 25155404, 9163586, 6188062) -

Feb 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 55 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with β-thalassemia (PMID: 2713503, 11559932, 23425204, 25155404). This variant is also known as IVS-II-745C>G or IVS2-745C>G. ClinVar contains an entry for this variant (Variation ID: 15457). Studies have shown that this variant alters HBB gene expression (PMID: 6188062). Studies have shown that this variant results in the activation of a cryptic splice site in intron 2 (PMID: 6188062). For these reasons, this variant has been classified as Pathogenic. -

Jun 08, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism. -

beta Thalassemia Pathogenic:5Other:1
Aug 18, 2011
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing;curation

- -

-
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 03, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Dec 09, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000518.4(HBB):c.316-106C>G(aka IVS2-745C>G) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 11559932 and 6188062. Classification of NM_000518.4(HBB):c.316-106C>G(aka IVS2-745C>G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Nov 25, 2019
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

Beta-thalassemia HBB/LCRB Pathogenic:3
Feb 01, 2024
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oct 09, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with HBB-related hemoglobinopathies, including beta thalassemia (OMIM). Dominant negative is also a suggested mechanism (PMID: 29700171). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable severity has been reported in sickle cell patients carrying the same variants (PMID: 31788855). In addition, clinical severity of beta-thalassemia patients is also dependent on whether variants in HBB are heterozygous, homozygous or compound heterozygous, and the amount of residual protein that is expressed (PMID: 20301599). (I) 0217 - Non-coding variant with known effect. RNA studies on transfected cells have shown that this variant creates a cryptic splice site within intron 2 leading to retention of 165bps of the intronic sequence (PMID: 6188062). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. It is one of the most common pathogenic Mediterranean variants in this gene and has been reported as homozygous or compound heterozygous in individuals with beta-thalassemia (PMIDs: 20301599, 31903828). This variant has also been reported in individuals with sickle cell disease when in compound heterozygous with the HbS variant (PMID: 31788855). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 05, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dominant beta-thalassemia Pathogenic:1
Feb 21, 2020
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS3, PM2, PM3, PP4, PP5. -

HBB-related disorder Pathogenic:1
May 27, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The HBB c.316-106C>G variant is predicted to interfere with splicing. This variant (also described as "IVS-II-745 C>G") has been reported in the heterozygous, compound heterozygous, and homozygous states in multiple individuals with beta thalassemia (Baysal et al. 1992. PubMed ID: 1390250; Sadiq et al. 2001. PubMed ID: 11559932; Ropero et al. 2013. PubMed ID: 23425204; Carrocini et al. 2017. PubMed ID: 28366028; Amin et al. 2020. PubMed ID: 33335418). It has also been observed to co-segregate with disease in a large, multi-generational family from the North Caucasus region currently living in Cyprus (Ergoren et al. 2021. PubMed ID: 33987626). Transcriptional analysis found that this variant leads to the formation of a cryptic splice donor site resulting in the insertion of 55 amino acid residues into the beta-globin mRNA (Treisman et al. 1983. PubMed ID: 6188062). This variant has not been reported in the gnomAD database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1
May 20, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hb SS disease Pathogenic:1
-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Beta-plus-thalassemia Pathogenic:1
Apr 15, 1982
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.68
DANN
Benign
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.72
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.72
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34690599; hg19: chr11-5247062; API