Genetic Variant NM_000184.3:c.19G>A (chr11-5254710-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000184.3(HBG2):c.19G>A(p.Glu7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000175 in 571,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

HBG2
NM_000184.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.33

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

hemoglobinopathy Toms River
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cyanosis, transient neonatal
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HBG2 links:

ENSG00000284931 (HGNC:):

ENSG00000284931 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3 link	c.19G>A	p.Glu7Lys	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.19G>A	p.Glu7Lys	missense_variant	Exon 1 of 3	1	NM_000184.3	ENSP00000338082.4	P69892
ENSG00000284931	ENST00000642908.1 link	c.19G>A	p.Glu7Lys	missense_variant	Exon 1 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7 link	n.*1322G>A		non_coding_transcript_exon_variant	Exon 7 of 8	5		ENSP00000369609.3	A0A2U3TZJ3
ENSG00000239920	ENST00000380259.7 link	n.*1322G>A		3_prime_UTR_variant	Exon 7 of 8	5		ENSP00000369609.3	A0A2U3TZJ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000175

AC:

AN:

571912

Hom.:

Cov.:

AF XY:

0.00000332

AC XY:

AN XY:

300850

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

15568

American (AMR)

AF:

0.00

AC:

AN:

26600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16082

East Asian (EAS)

AF:

0.00

AC:

AN:

32094

South Asian (SAS)

AF:

0.0000189

AC:

AN:

52912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2264

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

362336

Other (OTH)

AF:

0.00

AC:

AN:

30210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;.;T;.

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;D;D;.

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.3

.;.;M;.

PhyloP100

2.3

PROVEAN

Uncertain

-2.5

.;.;N;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0040

.;.;D;.

Sift4G

Benign

0.36

.;.;T;.

Polyphen

0.96

.;.;D;.

Vest4

0.21, 0.29

MutPred

0.52

Gain of methylation at E7 (P = 0.0123);Gain of methylation at E7 (P = 0.0123);Gain of methylation at E7 (P = 0.0123);Gain of methylation at E7 (P = 0.0123);

MVP

0.91

ClinPred

0.86

GERP RS

3.7

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.55

gMVP

0.23

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over