chr7-26196414-A-C

Variant names:

• chr7-26196414-A-C
• rs117082250
• NM_002137.4:c.645T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F215C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNRNPA2B1 NM_002137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.573
• Publications: 2 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26597345).

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.645T>G	p.Phe215Leu	missense	Exon 6 of 11	NP_002128.1	P22626-2
	HNRNPA2B1	NM_001438568.1		c.681T>G	p.Phe227Leu	missense	Exon 7 of 12	NP_001425497.1
	HNRNPA2B1	NM_001438569.1		c.681T>G	p.Phe227Leu	missense	Exon 7 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.645T>G	p.Phe215Leu	missense	Exon 6 of 11	ENSP00000478691.2	P22626-2
	HNRNPA2B1	ENST00000354667.8	TSL:1	c.681T>G	p.Phe227Leu	missense	Exon 7 of 12	ENSP00000346694.4	P22626-1
	HNRNPA2B1	ENST00000356674.8	TSL:1	c.681T>G	p.Phe227Leu	missense	Exon 7 of 11	ENSP00000349101.8	P22626-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251410 AF XY: 0.00000736

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 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 v4.9

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
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.57
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.47
Sift	Benign	0.037	D
Sift4G	Benign	0.12	T
Polyphen		0.33	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
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs117082250; hg19: chr7-26236034;