11-5254691-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000184.3(HBG2):c.38C>G(p.Thr13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000384 in 781,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 23)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

HBG2
NM_000184.3 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 0.373

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.

PM1

In a modified_residue Phosphothreonine (size 0) in uniprot entity HBG2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27287346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000184.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG2	NM_000184.3	MANE Select	c.38C>G	p.Thr13Arg	missense	Exon 1 of 3	NP_000175.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HBG2	ENST00000336906.6	TSL:1 MANE Select	c.38C>G	p.Thr13Arg	missense	Exon 1 of 3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1		c.38C>G	p.Thr13Arg	missense	Exon 1 of 3	ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	TSL:5	n.*1341C>G		non_coding_transcript_exon	Exon 7 of 8	ENSP00000369609.3

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

144880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000696

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:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000157

AC:

AN:

636332

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

332698

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:

17238

American (AMR)

AF:

0.00

AC:

AN:

29642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17204

East Asian (EAS)

AF:

0.00

AC:

AN:

32570

South Asian (SAS)

AF:

0.00

AC:

AN:

56540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2450

European-Non Finnish (NFE)

AF:

0.00000242

AC:

AN:

412456

Other (OTH)

AF:

0.00

AC:

AN:

32426

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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

AF:

0.0000138

AC:

AN:

144880

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

69950

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

39122

American (AMR)

AF:

0.0000696

AC:

AN:

14370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66132

Other (OTH)

AF:

0.00

AC:

AN:

1916

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:other

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

HEMOGLOBIN F (HEATHER) (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.061

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.074

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.27

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.8

PhyloP100

0.37

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Benign

0.16

Polyphen

0.75

Vest4

0.17

MutPred

0.47

Loss of methylation at K18 (P = 0.0597)

MVP

0.89

ClinPred

0.63

GERP RS

1.7

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.73

gMVP

0.23

Mutation Taster

=22/78

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over