11-5253363-C-G

Position:

• chr11-5253363-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000184.3(HBG2):​c.358G>C​(p.Gly120Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.128

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 Likely_benign. Variant got -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBG2	NM_000184.3	c.358G>C	p.Gly120Arg	missense_variant	3/3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.358G>C	p.Gly120Arg	missense_variant	3/3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.315+929G>C		intron_variant				ENSP00000495346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461544 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727112

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 20, 2021

The HBG2 c.358G>C; p.Gly120Arg variant (also known as Gly119Arg when numbered from the mature protein), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 120 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.512). However, given the lack of clinical and functional data, the significance of the p.Gly120Arg variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.85	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.9	.;M;.
PROVEAN	Pathogenic	-5.3	.;D;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	.;D;.
Sift4G	Uncertain	0.038	.;D;.
Polyphen		0.99	.;D;.
Vest4		0.37
MutPred		0.60		Gain of catalytic residue at G120 (P = 0.0538);Gain of catalytic residue at G120 (P = 0.0538);.;
MVP		0.97
ClinPred		1.0	D
GERP RS		0.89
Varity_R		0.74
gMVP		0.53

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-5274593;