chr11-5254725-C-G

Variant names:

• chr11-5254725-C-G
• rs36006195
• NM_000184.3:c.4G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000184.3(HBG2):​c.4G>C​(p.Gly2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• Publications: 10 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a modified_residue N-acetylglycine; in form Hb F1 (size 0) in uniprot entity HBG2_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.4G>C	p.Gly2Arg	missense_variant	Exon 1 of 3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.4G>C	p.Gly2Arg	missense_variant	Exon 1 of 3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.4G>C	p.Gly2Arg	missense_variant	Exon 1 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	n.*1307G>C		non_coding_transcript_exon_variant	Exon 7 of 8	5		ENSP00000369609.3
ENSG00000239920	ENST00000380259.7	n.*1307G>C		3_prime_UTR_variant	Exon 7 of 8	5		ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 6

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.040	.;.;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.65	T;T;T;.
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	0.55	.;.;N;.
PhyloP100		2.2
PROVEAN	Benign	-0.10	.;.;N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	.;.;D;.
Sift4G	Pathogenic	0.0010	.;.;D;.
Polyphen		0.14	.;.;B;.
Vest4		0.18, 0.19
MutPred		0.44		Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);
MVP		0.94
ClinPred		0.49	T
GERP RS		2.7
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.36
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs36006195; hg19: chr11-5275955;