chr11-5254486-T-C

Position:

• chr11-5254486-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000184.3(HBG2):​c.121A>G​(p.Arg41Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 4.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBG2	NM_000184.3	c.121A>G	p.Arg41Gly	missense_variant	2/3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.121A>G	p.Arg41Gly	missense_variant	2/3	1	NM_000184.3	ENSP00000338082	P1
HBG2	ENST00000444587.1	c.83A>G	p.Glu28Gly	missense_variant	2/3	2		ENSP00000488218
HBG2	ENST00000380252.6	c.-45A>G		5_prime_UTR_variant	2/3	3		ENSP00000369602

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN F (VELETA) Other:1

other, no assertion criteria provided

literature only

OMIM

Aug 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.44	T
MutationTaster	Benign	1.0	D;D;D
Vest4		0.43
ClinPred		1.0	D
GERP RS		3.9

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: rs34532478; hg19: chr11-5275716;