Genetic Variant HNRNPA2B1:p.Phe215Phe (chr7-26196414-A-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_002137.4(HNRNPA2B1):c.645T>C(p.Phe215Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,613,720 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0068 ( 54 hom. )

Consequence

HNRNPA2B1
NM_002137.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.573

Publications

2 publications found

Variant links:

Genes affected

HNRNPA2B1 (HGNC:5033): (heterogeneous nuclear ribonucleoprotein A2/B1) This gene belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms. [provided by RefSeq, Jul 2008]

HNRNPA2B1 Gene-Disease associations (from GenCC):

inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
oculopharyngeal muscular dystrophy 2
Inheritance: AD Classification: STRONG Submitted by: G2P
amyotrophic lateral sclerosis
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
inclusion body myopathy with Paget disease of bone and frontotemporal dementia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNRNPA2B1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 7-26196414-A-G is Benign according to our data. Variant chr7-26196414-A-G is described in ClinVar as Benign. ClinVar VariationId is 261955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.573 with no splicing effect.

BS2

High AC in GnomAd4 at 721 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002137.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNRNPA2B1	NM_002137.4	MANE Select	c.645T>C	p.Phe215Phe	synonymous	Exon 6 of 11	NP_002128.1	P22626-2
HNRNPA2B1	NM_001438568.1		c.681T>C	p.Phe227Phe	synonymous	Exon 7 of 12	NP_001425497.1
HNRNPA2B1	NM_001438569.1		c.681T>C	p.Phe227Phe	synonymous	Exon 7 of 12	NP_001425498.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNRNPA2B1	ENST00000618183.5	TSL:5 MANE Select	c.645T>C	p.Phe215Phe	synonymous	Exon 6 of 11	ENSP00000478691.2	P22626-2
HNRNPA2B1	ENST00000354667.8	TSL:1	c.681T>C	p.Phe227Phe	synonymous	Exon 7 of 12	ENSP00000346694.4	P22626-1
HNRNPA2B1	ENST00000356674.8	TSL:1	c.681T>C	p.Phe227Phe	synonymous	Exon 7 of 11	ENSP00000349101.8	P22626-1

Frequencies

GnomAD3 genomes

AF:

0.00473

AC:

720

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00482

AC:

1213

AN:

251410

AF XY:

0.00489

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00503

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00728

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00682

AC:

9974

AN:

1461396

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

4839

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33464

American (AMR)

AF:

0.00483

AC:

216

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00436

AC:

114

AN:

26128

East Asian (EAS)

AF:

0.000176

AC:

AN:

39692

South Asian (SAS)

AF:

0.00215

AC:

185

AN:

86238

European-Finnish (FIN)

AF:

0.00174

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00803

AC:

8925

AN:

1111590

Other (OTH)

AF:

0.00636

AC:

384

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

480

960

1440

1920

2400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

348

696

1044

1392

1740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00473

AC:

721

AN:

152324

Hom.:

Cov.:

AF XY:

0.00466

AC XY:

347

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41570

American (AMR)

AF:

0.00797

AC:

122

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5194

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00725

AC:

493

AN:

68020

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00642

Hom.:

Bravo

AF:

0.00465

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00698

EpiControl

AF:

0.00895

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.0

(source)

DANN

Benign

0.54

PhyloP100

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over