chr11-5254939-G-A

Variant names:

• chr11-5254939-G-A
• rs7482144
• ENST00000380259.7:n.*1093C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_StrongBP6_Strong

The ENST00000380252.6(HBG2):c.-73-425C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000380252.6 is not a MANE Select or MANE Plus Clinical transcript for HBG2; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.207 (AC=31,096) in the gnomAD database across 150,182 control chromosomes, including 15 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.26. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (15 hom., cov: 29)
  • Exomes 𝑓: 0.22 (1 hom.)
• Consequence: HBG2 ENST00000380252.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 0.541
• Publications: 20 publications found

Genes affected

ENSG00000239920 (HGNC:):

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):

• cyanosis, transient neonatal

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet
• hemoglobinopathy Toms River

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 15.; Very high cumulative gnomAD AC = 31096 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000380252.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HBG2 NM_000184.3	MANE Select	c.-211C>T	upstream_gene	N/A	Prot: NP_000175.1 UniProt:

HBG2 NM_000184.3

MANE Select

HGVSc / HGVSpc.-211C>T

Exon rankN/A

upstream_gene

Prot: NP_000175.1UniProt: P69892

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ENSG00000239920 ENST00000380259.7	TSL:5	n.*1093C>T	3_prime_UTR	Exon 7 of 8	Prot: ENSP00000369609.3 UniProt:
	ENSG00000239920 ENST00000380259.7	TSL:5	n.*1093C>T	non_coding_transcript_exon	Exon 7 of 8	Prot: ENSP00000369609.3 UniProt:
	HBG2 ENST00000380252.6	TSL:3	c.-73-425C>T	intron	Intron 1 of 2	Prot: ENSP00000369602.2 UniProt:

ENSG00000239920 ENST00000380259.7

TSL:5

HGVSc / HGVSpn.*1093C>T

Exon rankExon 7 of 8

3_prime_UTR

Prot: ENSP00000369609.3UniProt: A0A2U3TZJ3

ENSG00000239920 ENST00000380259.7

TSL:5

HGVSc / HGVSpn.*1093C>T

Exon rankExon 7 of 8

non_coding_transcript_exon

Prot: ENSP00000369609.3UniProt: A0A2U3TZJ3

HBG2 ENST00000380252.6

TSL:3

HGVSc / HGVSpc.-73-425C>T

Exon rankIntron 1 of 2

intron

Prot: ENSP00000369602.2UniProt: E9PBW4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.207	AC:31089	Hom:15	AN:150068	Cov:29
GnomAD4 exome Warning	AF: 0.218	AC:89641	Hom:1	AN:410562	Cov:0
GnomAD4 genome	AF: 0.207	AC:31096	Hom:15	AN:150182	Cov:29
TOPMed (Bravo)	AF: 0.204	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.258	AC:17208	Hom:1772	AN:66722	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.134	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 1.00	AC:118	Hom:	AN:118	Cov:
Qatari Genome	AF: 0.171	AC:30	Hom:	AN:176	Cov:
Turkish Variome	AF: 0.208	AC:314	Hom:2	AN:1508	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.141	8510	60218	0.140	13476	96184

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Hereditary persistence of fetal hemoglobin (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.9
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.75
GPN-Star LLR	N/A	-1.1
GPN-Star score	N/A	1.1
Mutation Taster	N/A	296/4	polymorphism
PhyloP100	Benign	0.54
PromoterAI	N/A	0.073	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs7482144;

hg19: chr11-5276169;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar