11-5253487-A-C

Variant names:

• chr11-5253487-A-C
• rs2070972
• NM_000184.3:c.316-82T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000184.3(HBG2):​c.316-82T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,256,676 control chromosomes in the GnomAD database, including 149,289 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.48 (15514 hom., cov: 31)
  • Exomes 𝑓: 0.48 (133775 hom.)
• Consequence: HBG2 NM_000184.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 8 publications found

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)

ENSG00000284931 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.316-82T>G		intron_variant	Intron 2 of 2	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.316-82T>G		intron_variant	Intron 2 of 2	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.315+805T>G		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes AF: 0.480 AC: 68065 AN: 141676 Hom.: 15501 Cov.: 31

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.783

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.610

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.521

GnomAD4 exome AF: 0.484 AC: 540133 AN: 1114896 Hom.: 133775 AF XY: 0.487 AC XY: 275726 AN XY: 566448

African (AFR) AF: 0.298 AC: 6907 AN: 23150

American (AMR) AF: 0.620 AC: 24394 AN: 39360

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 14630 AN: 23528

East Asian (EAS) AF: 0.732 AC: 27013 AN: 36890

South Asian (SAS) AF: 0.546 AC: 41803 AN: 76568

European-Finnish (FIN) AF: 0.466 AC: 23863 AN: 51192

Middle Eastern (MID) AF: 0.609 AC: 2929 AN: 4812

European-Non Finnish (NFE) AF: 0.461 AC: 374110 AN: 810890

Other (OTH) AF: 0.505 AC: 24484 AN: 48506

GnomAD4 genome AF: 0.480 AC: 68117 AN: 141780 Hom.: 15514 Cov.: 31 AF XY: 0.485 AC XY: 33731 AN XY: 69550

African (AFR) AF: 0.378 AC: 12508 AN: 33096

American (AMR) AF: 0.590 AC: 8787 AN: 14890

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2162 AN: 3420

East Asian (EAS) AF: 0.784 AC: 4001 AN: 5106

South Asian (SAS) AF: 0.555 AC: 2611 AN: 4704

European-Finnish (FIN) AF: 0.463 AC: 4855 AN: 10484

Middle Eastern (MID) AF: 0.594 AC: 171 AN: 288

European-Non Finnish (NFE) AF: 0.471 AC: 31500 AN: 66884

Other (OTH) AF: 0.523 AC: 1048 AN: 2004

Alfa AF: 0.453 Hom.: 1602

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.8
DANN	Benign	0.44
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070972; hg19: chr11-5274717;