Genetic Variant HBG2:p.Lys9Gln (chr11-5254704-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000184.3(HBG2):c.25A>C(p.Lys9Gln) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K9E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 23)

Failed GnomAD Quality Control

Consequence

HBG2
NM_000184.3 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 4.64

Variant links:

Genes affected

HBG2 (HGNC:4832): (hemoglobin subunit gamma 2) The gamma globin genes (HBG1 and HBG2) are normally expressed in the fetal liver, spleen and bone marrow. Two gamma chains together with two alpha chains constitute fetal hemoglobin (HbF) which is normally replaced by adult hemoglobin (HbA) at birth. In some beta-thalassemias and related conditions, gamma chain production continues into adulthood. The two types of gamma chains differ at residue 136 where glycine is found in the G-gamma product (HBG2) and alanine is found in the A-gamma product (HBG1). The former is predominant at birth. 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]

HBG2 links:

ENSG00000284931 (HGNC:):

ENSG00000284931 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20655343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3 link	c.25A>C	p.Lys9Gln	missense_variant	Exon 1 of 3	ENST00000336906.6	NP_000175.1	P69892D9YZU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBG2	ENST00000336906.6 link	c.25A>C	p.Lys9Gln	missense_variant	Exon 1 of 3	1	NM_000184.3	ENSP00000338082.4	P69892
ENSG00000284931	ENST00000642908.1 link	c.25A>C	p.Lys9Gln	missense_variant	Exon 1 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7 link	n.*1328A>C		non_coding_transcript_exon_variant	Exon 7 of 8	5		ENSP00000369609.3	A0A2U3TZJ3
ENSG00000239920	ENST00000380259.7 link	n.*1328A>C		3_prime_UTR_variant	Exon 7 of 8	5		ENSP00000369609.3	A0A2U3TZJ3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

144702

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

82226

Hom.:

AF XY:

0.00

AC XY:

AN XY:

42478

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

144808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69988

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:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000239

AC:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN F (ALBAICIN)

Other:1

Aug 18, 2016

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

Benign

0.28

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

.;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

D;D;D;.

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

4.0

.;.;H;.

PROVEAN

Uncertain

-3.1

.;.;D;.

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Uncertain

0.0030

.;.;D;.

Polyphen

0.97

.;.;D;.

Vest4

0.51, 0.51

MutPred

0.70

Loss of methylation at K9 (P = 0.0061);Loss of methylation at K9 (P = 0.0061);Loss of methylation at K9 (P = 0.0061);Loss of methylation at K9 (P = 0.0061);

MVP

0.91

ClinPred

0.99

GERP RS

2.6

Varity_R

0.82

gMVP

0.57

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over