7-26197618-A-G

Variant names:

• chr7-26197618-A-G
• rs41275982
• NM_002137.4:c.117+4T>C

Variant summary

Our verdict is Benign. The variant received -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 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.00002346
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.423
• Publications: 7 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, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• oculopharyngeal muscular dystrophy 2

  Inheritance: AD Classification: STRONG Submitted by: G2P
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen
• inclusion body myopathy with Paget disease of bone and frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4609 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA2B1	NM_002137.4	MANE Select	c.117+4T>C		splice_region intron	N/A	NP_002128.1
	HNRNPA2B1	NM_001438568.1		c.153+4T>C		splice_region intron	N/A	NP_001425497.1
	HNRNPA2B1	NM_001438569.1		c.153+4T>C		splice_region intron	N/A	NP_001425498.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA2B1	ENST00000618183.5	TSL:5 MANE Select	c.117+4T>C		splice_region intron	N/A	ENSP00000478691.2
	HNRNPA2B1	ENST00000354667.8	TSL:1	c.153+4T>C		splice_region intron	N/A	ENSP00000346694.4
	HNRNPA2B1	ENST00000356674.8	TSL:1	c.153+4T>C		splice_region intron	N/A	ENSP00000349101.8

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

GnomAD2 exomes AF: 0.0289 AC: 7221 AN: 250034 AF XY: 0.0290

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 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

African (AFR) AF: 0.0299 AC: 993 AN: 33262

American (AMR) AF: 0.0230 AC: 1025 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.0658 AC: 1715 AN: 26050

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39622

South Asian (SAS) AF: 0.0160 AC: 1370 AN: 85790

European-Finnish (FIN) AF: 0.0240 AC: 1282 AN: 53382

Middle Eastern (MID) AF: 0.0524 AC: 302 AN: 5758

European-Non Finnish (NFE) AF: 0.0335 AC: 36992 AN: 1104682

Other (OTH) AF: 0.0340 AC: 2046 AN: 60132

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

African (AFR) AF: 0.0279 AC: 1158 AN: 41566

American (AMR) AF: 0.0272 AC: 416 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0596 AC: 207 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0151 AC: 73 AN: 4834

European-Finnish (FIN) AF: 0.0237 AC: 252 AN: 10622

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0354 AC: 2409 AN: 68030

Other (OTH) AF: 0.0350 AC: 74 AN: 2116

Alfa AF: 0.0342 Hom.: 85

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Sep 09, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.3
DANN	Benign	0.71
PhyloP100		-0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41275982; hg19: chr7-26237238;