rs397515326

Variant names:

• chr7-26193346-T-A
• rs397515326
• NM_002137.4:c.869A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002137.4(HNRNPA2B1):​c.869A>T​(p.Asp290Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPA2B1 NM_002137.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.10
• Publications: 64 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 7-26193346-T-A is Pathogenic according to our data. Variant chr7-26193346-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 65454.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA2B1	NM_002137.4	MANE Select	c.869A>T	p.Asp290Val	missense	Exon 9 of 11	NP_002128.1
	HNRNPA2B1	NM_001438568.1		c.905A>T	p.Asp302Val	missense	Exon 10 of 12	NP_001425497.1
	HNRNPA2B1	NM_001438569.1		c.905A>T	p.Asp302Val	missense	Exon 10 of 12	NP_001425498.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA2B1	ENST00000618183.5	TSL:5 MANE Select	c.869A>T	p.Asp290Val	missense	Exon 9 of 11	ENSP00000478691.2
	HNRNPA2B1	ENST00000354667.8	TSL:1	c.905A>T	p.Asp302Val	missense	Exon 10 of 12	ENSP00000346694.4
	HNRNPA2B1	ENST00000356674.8	TSL:1	c.905A>T	p.Asp302Val	missense	Exon 10 of 11	ENSP00000349101.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.45		Gain of sheet (P = 0.0028)
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.97
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397515326; hg19: chr7-26232966;