16-172963-G-C

Position:

• chr16-172963-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_000517.6(HBA2):​c.51G>C​(p.Lys17Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 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. K17E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 2)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.396

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 9 uncertain in NM_000517.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.51G>C	p.Lys17Asn	missense_variant	1/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.51G>C	p.Lys17Asn	missense_variant	1/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1	c.21G>C	p.Lys7Asn	missense_variant	1/2	1
HBA2	ENST00000482565.1	n.70G>C		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-2+5G>C		splice_donor_5th_base_variant, intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.21	N
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	0.81	D;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.80
MutPred		0.84		Loss of ubiquitination at K17 (P = 0.0255);
MVP		1.0
MPC		2.4
ClinPred		0.96	D
GERP RS		3.9
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs281860619; hg19: chr16-222962;