rs34019507

Variant names:

• chr11-5254409-C-A
• rs34019507
• NM_000184.3:c.198G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-5254409-C-A
• chr11-5254409-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000184.3(HBG2):​c.198G>T​(p.Lys66Asn) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508
• Publications: 2 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 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, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.198G>T	p.Lys66Asn	missense_variant	Exon 2 of 3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.198G>T	p.Lys66Asn	missense_variant	Exon 2 of 3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.198G>T	p.Lys66Asn	missense_variant	Exon 2 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	n.*1501G>T		non_coding_transcript_exon_variant	Exon 8 of 8	5		ENSP00000369609.3
ENSG00000239920	ENST00000380259.7	n.*1501G>T		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000369609.3

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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	.;.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.4	.;.;M;.
PhyloP100		0.51
PROVEAN	Uncertain	-3.9	.;.;D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	.;.;D;.
Sift4G	Uncertain	0.026	.;.;D;.
Polyphen		0.87	.;.;P;.
Vest4		0.48
MutPred		0.70		Gain of catalytic residue at K66 (P = 0.0506);Gain of catalytic residue at K66 (P = 0.0506);Gain of catalytic residue at K66 (P = 0.0506);.;
MVP		0.96
ClinPred		0.99	D
GERP RS		3.1
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3
Varity_R		0.72
gMVP		0.61
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs34019507; hg19: chr11-5275639;