chr11-5254407-T-A

Position:

• chr11-5254407-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000184.3(HBG2):​c.200A>T​(p.Lys67Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. K67R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000184.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBG2	NM_000184.3	c.200A>T	p.Lys67Met	missense_variant	2/3	ENST00000336906.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBG2	ENST00000336906.6	c.200A>T	p.Lys67Met	missense_variant	2/3	1	NM_000184.3	P1
HBG2	ENST00000380252.6	c.35A>T	p.Lys12Met	missense_variant	2/3	3
HBG2	ENST00000444587.1	c.*69A>T		3_prime_UTR_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	.;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	.;.;H;.
MutationTaster	Benign	0.96	D;D;D
PROVEAN	Pathogenic	-5.4	.;.;D;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.0020	.;.;D;.
Polyphen		1.0	.;.;D;.
Vest4		0.59
MutPred		0.91		Loss of disorder (P = 0.0287);Loss of disorder (P = 0.0287);Loss of disorder (P = 0.0287);.;
MVP		0.96
ClinPred		0.99	D
GERP RS		2.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.82
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs35481866; hg19: chr11-5275637;