chr7-26197618-A-G

Position:

• chr7-26197618-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002137.4(HNRNPA2B1):​c.117+4T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,605,510 control chromosomes in the GnomAD database, including 911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (80 hom., cov: 32)
  • Exomes 𝑓: 0.031 (831 hom.)
• Consequence: HNRNPA2B1 NM_002137.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002346
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.423

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-26197618-A-G is Benign according to our data. Variant chr7-26197618-A-G is described in ClinVar as [Benign]. Clinvar id is 261953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-26197618-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0303 (4609/152336) while in subpopulation NFE AF= 0.0354 (2409/68030). AF 95% confidence interval is 0.0342. There are 80 homozygotes in gnomad4. There are 2176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4609 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPA2B1	NM_002137.4	c.117+4T>C		splice_donor_region_variant, intron_variant		ENST00000618183.5	NP_002128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPA2B1	ENST00000618183.5	c.117+4T>C		splice_donor_region_variant, intron_variant		5	NM_002137.4	ENSP00000478691	A1

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4604 AN: 152218 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0596

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0354

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0289 AC: 7221 AN: 250034 Hom.: 136 AF XY: 0.0290 AC XY: 3925 AN XY: 135196

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0601

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.0161

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0368

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0315 AC: 45729 AN: 1453174 Hom.: 831 Cov.: 29 AF XY: 0.0312 AC XY: 22537 AN XY: 723360

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.0230

Gnomad4 ASJ exome AF: 0.0658

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0160

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.0335

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0303 AC: 4609 AN: 152336 Hom.: 80 Cov.: 32 AF XY: 0.0292 AC XY: 2176 AN XY: 74492

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.0272

Gnomad4 ASJ AF: 0.0596

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0354

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0344 Hom.: 75

Bravo AF: 0.0307

Asia WGS AF: 0.0130 AC: 47 AN: 3478

EpiCase AF: 0.0371

EpiControl AF: 0.0356

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.3
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0080
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: rs41275982; hg19: chr7-26237238;