Genetic Variant NM_000184.3:c.304G>C (chr11-5254303-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000184.3(HBG2):c.304G>C(p.Glu102Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E102K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBG2
NM_000184.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.97

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3 link	c.304G>C	p.Glu102Gln	missense_variant	Exon 2 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.304G>C	p.Glu102Gln	missense_variant	Exon 2 of 3	1	NM_000184.3	ENSP00000338082.4	P69892
ENSG00000284931	ENST00000642908.1 link	c.304G>C	p.Glu102Gln	missense_variant	Exon 2 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7 link	n.*1607G>C		downstream_gene_variant		5		ENSP00000369609.3	A0A2U3TZJ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

.;.;T;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

D;T;T;T

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.4

.;.;M;.

PROVEAN

Benign

-2.1

.;.;N;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.014

.;.;D;.

Sift4G

Benign

0.12

.;.;T;.

Polyphen

0.80

.;.;P;.

Vest4

0.70

MutPred

0.91

Loss of ubiquitination at K105 (P = 0.048);Loss of ubiquitination at K105 (P = 0.048);Loss of ubiquitination at K105 (P = 0.048);.;

MVP

0.91

ClinPred

0.87

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.67

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over