7-26193569-T-C

Variant names:

• chr7-26193569-T-C
• rs144309126
• NM_002137.4:c.841+6A>G

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.841+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,578,182 control chromosomes in the GnomAD database, including 16 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 0.0058 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (6 hom.)
• Consequence: HNRNPA2B1 NM_002137.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004119
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.143
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 7-26193569-T-C is Benign according to our data. Variant chr7-26193569-T-C is described in ClinVar as Benign. ClinVar VariationId is 541429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00575 (876/152288) while in subpopulation AFR AF = 0.0198 (822/41546). AF 95% confidence interval is 0.0187. There are 10 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 876 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA2B1	NM_002137.4	MANE Select	c.841+6A>G		splice_region intron	N/A	NP_002128.1
	HNRNPA2B1	NM_001438568.1		c.877+6A>G		splice_region intron	N/A	NP_001425497.1
	HNRNPA2B1	NM_001438569.1		c.877+6A>G		splice_region intron	N/A	NP_001425498.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA2B1	ENST00000618183.5	TSL:5 MANE Select	c.841+6A>G		splice_region intron	N/A	ENSP00000478691.2
	HNRNPA2B1	ENST00000354667.8	TSL:1	c.877+6A>G		splice_region intron	N/A	ENSP00000346694.4
	HNRNPA2B1	ENST00000356674.8	TSL:1	c.877+6A>G		splice_region intron	N/A	ENSP00000349101.8

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152170 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00165 AC: 360 AN: 217804 AF XY: 0.00125

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000627

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000286

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.000538 AC: 767 AN: 1425894 Hom.: 6 Cov.: 31 AF XY: 0.000477 AC XY: 338 AN XY: 708570

African (AFR) AF: 0.0187 AC: 577 AN: 30870

American (AMR) AF: 0.00197 AC: 63 AN: 31974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24364

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39320

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5660

European-Non Finnish (NFE) AF: 0.0000409 AC: 45 AN: 1101432

Other (OTH) AF: 0.00132 AC: 78 AN: 58914

GnomAD4 genome AF: 0.00575 AC: 876 AN: 152288 Hom.: 10 Cov.: 32 AF XY: 0.00560 AC XY: 417 AN XY: 74470

African (AFR) AF: 0.0198 AC: 822 AN: 41546

American (AMR) AF: 0.00255 AC: 39 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00322 Hom.: 4

Bravo AF: 0.00641

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	HNRNPA2B1-related disorder (1)
-	-	1	Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.73
PhyloP100		-0.14
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.064
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: rs144309126; hg19: chr7-26233189;