rs117082250

Positions:

• chr7-26196414-A-C
• chr7-26196414-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002137.4(HNRNPA2B1):​c.645T>G​(p.Phe215Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F215F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNRNPA2B1 NM_002137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.573

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26597345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPA2B1	NM_002137.4	c.645T>G	p.Phe215Leu	missense_variant	6/11	ENST00000618183.5	NP_002128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPA2B1	ENST00000618183.5	c.645T>G	p.Phe215Leu	missense_variant	6/11	5	NM_002137.4	ENSP00000478691.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251410 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135894

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Benign	0.30	.;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	.;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	.;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.037	.;D;D
Sift4G	Benign	0.12	.;T;T
Polyphen		0.33	B;B;B
Vest4		0.52
MutPred		0.36		.;Gain of glycosylation at S225 (P = 0.0928);.;
MVP		0.80
MPC		1.3
ClinPred		0.33	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs117082250; hg19: chr7-26236034;