chr11-5226706-C-G

Variant names:

• chr11-5226706-C-G
• rs34446260
• NM_000518.5:c.186G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP3_Moderate BP6

The NM_000518.5(HBB):​c.186G>C​(p.Lys62Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K62Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: -1.90
• Publications: 2 publications found

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]

HBB Gene-Disease associations (from GenCC):

• dominant beta-thalassemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia intermedia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia major

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-beta-thalassemia disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin c disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin d disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin E disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 30 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• BP6: Variant 11-5226706-C-G is Benign according to our data. Variant chr11-5226706-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15196.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.186G>C	p.Lys62Asn	missense_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.186G>C	p.Lys62Asn	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

May 01, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.186G>C (p.Lys62Asn) results in a non-conservative amino acid change located in the Globin (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251438 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.186G>C in individuals affected with Hemoglobinopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign and another as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Hikari (HBB: c.186G>C; p.Lys62Asn, also known as Lys61Asn when numbered from the mature protein; rs34446260, HbVar ID: 354) is reported in the literature in the heterozygous state in individuals without reported hematological abnormalities (Nakatsuji 1981, HbVar and references therein). This variant is reported in ClinVar (Variation ID: 15196) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The lysine at codon 62 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.622). Further, functional analyses indicate that the variant protein is stable and exhibits normal oxygen-binding properties (Nakatsuji 1981). Based on available information, the Hb Hikari variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Nakatsuji T et al. A further example of hemoglobin Hikari (beta 61[E5] Lys replaced by Asn). Hemoglobin. 1981;5(5):487-92. PMID: 6792159. -

HEMOGLOBIN HIKARI Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.85	.;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
PhyloP100		-1.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D;.;.;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.057	T;.;.;.
Polyphen		0.75	P;P;.;.
Vest4		0.56
MutPred		0.88		Loss of methylation at K62 (P = 0.013);Loss of methylation at K62 (P = 0.013);Loss of methylation at K62 (P = 0.013);Loss of methylation at K62 (P = 0.013);
MVP		0.97
MPC		0.14
ClinPred		0.93	D
GERP RS		2.2
PromoterAI		-0.0039	Neutral
Varity_R		0.71
gMVP		0.81
Mutation Taster		=14/86	disease causing

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: rs34446260; hg19: chr11-5247936;