chrX-101412725-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_019597.5(HNRNPH2):c.737A>G(p.Tyr246Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,097,911 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )
Consequence
HNRNPH2
NM_019597.5 missense
NM_019597.5 missense
Scores
2
6
9
Clinical Significance
Conservation
PhyloP100: 5.49
Genes affected
HNRNPH2 (HGNC:5042): (heterogeneous nuclear ribonucleoprotein H2) This gene belongs to the 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 three repeats of quasi-RRM domains that binds to RNAs. It is very similar to the family member HNRPH1. This gene is thought to be involved in Fabray disease and X-linked agammaglobulinemia phenotype. Alternative splicing results in multiple transcript variants encoding the same protein. Read-through transcription between this locus and the ribosomal protein L36a gene has been observed. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a modified_residue Phosphotyrosine (size 0) in uniprot entity HNRH2_HUMAN
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, HNRNPH2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.76
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNRNPH2 | NM_019597.5 | c.737A>G | p.Tyr246Cys | missense_variant | 2/2 | ENST00000316594.6 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.*733A>G | 3_prime_UTR_variant | 5/5 | |||
HNRNPH2 | NM_001032393.3 | c.737A>G | p.Tyr246Cys | missense_variant | 2/2 | ||
RPL36A-HNRNPH2 | NM_001199974.2 | c.*733A>G | 3_prime_UTR_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNRNPH2 | ENST00000316594.6 | c.737A>G | p.Tyr246Cys | missense_variant | 2/2 | 1 | NM_019597.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome AF: 0.00000182 AC: 2AN: 1097911Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 363267
GnomAD4 exome
AF:
AC:
2
AN:
1097911
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
363267
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, X-linked, syndromic, Bain type Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 24, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of phosphorylation at Y246 (P = 0.0402);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at