rs397515326

Positions:

• chr7-26193346-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a mutagenesis_site Impairs hydrogel-binding. (size 0) in uniprot entity ROA2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HNRNPA2B1. . Gene score misZ 3.0018 (greater than the threshold 3.09). Trascript score misZ 3.7844 (greater than threshold 3.09). GenCC has associacion of gene with inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, amyotrophic lateral sclerosis, inclusion body myopathy with Paget disease of bone and frontotemporal dementia.
• 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 id is 65454.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPA2B1	NM_002137.4	c.869A>T	p.Asp290Val	missense_variant	9/11	ENST00000618183.5	NP_002128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPA2B1	ENST00000618183.5	c.869A>T	p.Asp290Val	missense_variant	9/11	5	NM_002137.4	ENSP00000478691	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Pathogenic	3.3	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	.;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	.;D;D
Sift4G	Uncertain	0.0020	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.81, 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

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

Other links and lift over

dbSNP: rs397515326; hg19: chr7-26232966;