rs35717854

Variant names:

• chr11-5254292-C-G
• rs35717854
• NM_000184.3:c.315G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000184.3(HBG2):​c.315G>C​(p.Lys105Asn) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBG2 NM_000184.3 missense, splice_region
• Scores: Splicing: ADA: 0.9194
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 1.37
• Publications: 1 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.315G>C	p.Lys105Asn	missense_variant, splice_region_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.315G>C	p.Lys105Asn	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.315G>C	p.Lys105Asn	missense_variant, splice_region_variant	Exon 2 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	n.*1618G>C		downstream_gene_variant		5		ENSP00000369609.3

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 (MACEDONIA II) Other:1

Aug 05, 2011

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	.;.;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.0040
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.9	.;.;M;.
PhyloP100		1.4
PROVEAN	Uncertain	-2.8	.;.;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.021	.;.;D;D
Sift4G	Uncertain	0.016	.;.;D;.
Polyphen		0.50	.;.;P;.
Vest4		0.75
MutPred		0.73		Loss of methylation at K105 (P = 0.0011);Loss of methylation at K105 (P = 0.0011);Loss of methylation at K105 (P = 0.0011);.;
MVP		0.91
ClinPred		0.97	D
GERP RS		2.2
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.79
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.61
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: rs35717854; hg19: chr11-5275522;