rs281864893

Positions:

• chr11-5254710-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33

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]

ENSG00000284931 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
HBG2	NM_000184.3	c.19G>A	p.Glu7Lys	missense_variant	1/3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.19G>A	p.Glu7Lys	missense_variant	1/3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.19G>A	p.Glu7Lys	missense_variant	1/3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	n.*1322G>A		non_coding_transcript_exon_variant	7/8	5		ENSP00000369609.3
ENSG00000239920	ENST00000380259.7	n.*1322G>A		3_prime_UTR_variant	7/8	5		ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000175 AC: 1 AN: 571912 Hom.: 0 Cov.: 7 AF XY: 0.00000332 AC XY: 1 AN XY: 300850

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: 0.0000189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D;D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.3	.;.;M;.
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	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.55
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs281864893; hg19: chr11-5275940;