rs63751196

Positions:

chr11-5254667-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBS2_Supporting

The NM_000184.3(HBG2):c.62T>C(p.Val21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 861,492 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.00018 ( 1 hom., cov: 23)

Exomes 𝑓: 0.00030 ( 2 hom. )

Consequence

HBG2
NM_000184.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.431

Variant links:

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 links:

ENSG00000284931 (HGNC:):

ENSG00000284931 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009400457).

BP6

Variant 11-5254667-A-G is Benign according to our data. Variant chr11-5254667-A-G is described in ClinVar as [Benign]. Clinvar id is 1685226.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 26 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBG2	NM_000184.3 linkuse as main transcript	c.62T>C	p.Val21Ala	missense_variant	1/3	ENST00000336906.6	NP_000175.1	P69892D9YZU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBG2	ENST00000336906.6 linkuse as main transcript	c.62T>C	p.Val21Ala	missense_variant	1/3	1	NM_000184.3	ENSP00000338082.4	P69892
ENSG00000284931	ENST00000642908.1 linkuse as main transcript	c.62T>C	p.Val21Ala	missense_variant	1/3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7 linkuse as main transcript	n.*1365T>C		non_coding_transcript_exon_variant	7/8	5		ENSP00000369609.3	A0A2U3TZJ3
ENSG00000239920	ENST00000380259.7 linkuse as main transcript	n.*1365T>C		3_prime_UTR_variant	7/8	5		ENSP00000369609.3	A0A2U3TZJ3

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

145264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00552

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000542

AC:

AN:

101540

Hom.:

AF XY:

0.000714

AC XY:

AN XY:

53194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00411

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000304

AC:

218

AN:

716116

Hom.:

Cov.:

AF XY:

0.000441

AC XY:

164

AN XY:

371962

show subpopulations

Gnomad4 AFR exome

AF:

0.0000524

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00339

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000210

Gnomad4 OTH exome

AF:

0.000255

GnomAD4 genome

AF:

0.000179

AC:

AN:

145376

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

70338

show subpopulations

Gnomad4 AFR

AF:

0.0000254

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00552

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000484

Hom.:

ExAC

AF:

0.000177

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

.;.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.0094

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.96

.;.;L

PROVEAN

Uncertain

-2.6

.;.;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.012

.;.;D

Sift4G

Benign

0.49

.;.;T

Polyphen

0.73

.;.;P

Vest4

0.47

MutPred

0.77

Gain of disorder (P = 0.036);Gain of disorder (P = 0.036);Gain of disorder (P = 0.036);

MVP

0.88

ClinPred

0.20

GERP RS

2.5

Varity_R

0.36

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over