11-5254177-T-C

Variant names:

• chr11-5254177-T-C
• rs2070973
• NM_000184.3:c.315+115A>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.315+115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,087,456 control chromosomes in the GnomAD database, including 90,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.44 (15832 hom., cov: 33)
  • Exomes 𝑓: 0.36 (75019 hom.)
• Consequence: HBG2 NM_000184.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG2	NM_000184.3	MANE Select	c.315+115A>G		intron	N/A	NP_000175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG2	ENST00000336906.6	TSL:1 MANE Select	c.315+115A>G		intron	N/A	ENSP00000338082.4
	ENSG00000284931	ENST00000642908.1		c.315+115A>G		intron	N/A	ENSP00000495346.1
	ENSG00000284931	ENST00000647543.1		c.315+115A>G		intron	N/A	ENSP00000496470.1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 65471 AN: 149366 Hom.: 15818 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.495

GnomAD4 exome AF: 0.357 AC: 334771 AN: 937978 Hom.: 75019 AF XY: 0.369 AC XY: 177264 AN XY: 479898

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

African (AFR) AF: 0.194 AC: 4987 AN: 25692

American (AMR) AF: 0.592 AC: 20167 AN: 34054

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 12110 AN: 20646

East Asian (EAS) AF: 0.707 AC: 23800 AN: 33676

South Asian (SAS) AF: 0.494 AC: 33339 AN: 67474

European-Finnish (FIN) AF: 0.452 AC: 22479 AN: 49772

Middle Eastern (MID) AF: 0.543 AC: 2139 AN: 3938

European-Non Finnish (NFE) AF: 0.301 AC: 198649 AN: 660778

Other (OTH) AF: 0.408 AC: 17101 AN: 41948

⚠️ 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.

GnomAD4 genome AF: 0.438 AC: 65523 AN: 149478 Hom.: 15832 Cov.: 33 AF XY: 0.445 AC XY: 32498 AN XY: 73076

African (AFR) AF: 0.264 AC: 10552 AN: 40004

American (AMR) AF: 0.578 AC: 8689 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2134 AN: 3434

East Asian (EAS) AF: 0.775 AC: 3987 AN: 5146

South Asian (SAS) AF: 0.540 AC: 2561 AN: 4742

European-Finnish (FIN) AF: 0.459 AC: 4820 AN: 10510

Middle Eastern (MID) AF: 0.583 AC: 169 AN: 290

European-Non Finnish (NFE) AF: 0.462 AC: 31104 AN: 67326

Other (OTH) AF: 0.498 AC: 1035 AN: 2080

Alfa AF: 0.435 Hom.: 1631

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.6
DANN	Benign	0.55
PhyloP100		-0.32
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: rs2070973; hg19: chr11-5275407;