11-5253037-C-T

Variant names:

• chr11-5253037-C-T
• rs2236794
• ENST00000642908.1:c.315+1255G>A

Variant summary

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

The ENST00000642908.1(ENSG00000284931):​c.315+1255G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 151,970 control chromosomes in the GnomAD database, including 15,562 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 0.43 (15562 hom., cov: 33)
• Consequence: ENSG00000284931 ENST00000642908.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.431
• Publications: 2 publications found

Genes affected

ENSG00000284931 (HGNC:):

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.*240G>A		downstream_gene_variant		ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000284931	ENST00000642908.1	c.315+1255G>A		intron_variant	Intron 2 of 2			ENSP00000495346.1
ENSG00000284931	ENST00000647543.1	c.378+306G>A		intron_variant	Intron 3 of 3			ENSP00000496470.1
HBG2	ENST00000336906.6	c.*240G>A		downstream_gene_variant		1	NM_000184.3	ENSP00000338082.4
HBG2	ENST00000380252.6	c.*240G>A		downstream_gene_variant		3		ENSP00000369602.2

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65024 AN: 151852 Hom.: 15549 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.488

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.428 AC: 65074 AN: 151970 Hom.: 15562 Cov.: 33 AF XY: 0.435 AC XY: 32280 AN XY: 74238

African (AFR) AF: 0.229 AC: 9475 AN: 41444

American (AMR) AF: 0.572 AC: 8721 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2158 AN: 3468

East Asian (EAS) AF: 0.779 AC: 4029 AN: 5172

South Asian (SAS) AF: 0.549 AC: 2645 AN: 4814

European-Finnish (FIN) AF: 0.462 AC: 4872 AN: 10546

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31491 AN: 67958

Other (OTH) AF: 0.490 AC: 1032 AN: 2106

Alfa AF: 0.458 Hom.: 10009

Bravo AF: 0.425

Asia WGS AF: 0.597 AC: 2077 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.69
DANN	Benign	0.48
PhyloP100		-0.43
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2236794; hg19: chr11-5274267;