7-26196414-A-G

Position:

• chr7-26196414-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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]

ACMG classification

Verdict is Benign. Variant got -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 id is 261955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-26196414-A-G is described in Lovd as [Benign]. Variant chr7-26196414-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.573 with no splicing effect.
• BS2: High AC in GnomAd4 at 721 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPA2B1	NM_002137.4	c.645T>C	p.Phe215Phe	synonymous_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>C	p.Phe215Phe	synonymous_variant	6/11	5	NM_002137.4	ENSP00000478691.2

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 720 AN: 152206 Hom.: 4 Cov.: 33

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

GnomAD3 exomes AF: 0.00482 AC: 1213 AN: 251410 Hom.: 4 AF XY: 0.00489 AC XY: 665 AN XY: 135894

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 SAS exome AF: 0.00252

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.: 54 Cov.: 31 AF XY: 0.00666 AC XY: 4839 AN XY: 727006

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00215

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00803

Gnomad4 OTH exome AF: 0.00636

GnomAD4 genome AF: 0.00473 AC: 721 AN: 152324 Hom.: 4 Cov.: 33 AF XY: 0.00466 AC XY: 347 AN XY: 74488

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00725

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00642 Hom.: 2

Bravo AF: 0.00465

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00895

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	HNRNPA2B1: BP4, BP7, BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.0
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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;