chrX-101412757-T-A
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2
The NM_019597.5(HNRNPH2):c.769T>A(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,208,274 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 131 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_019597.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNRNPH2 | NM_019597.5 | c.769T>A | p.Ser257Thr | missense_variant | 2/2 | ENST00000316594.6 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.*765T>A | 3_prime_UTR_variant | 5/5 | |||
HNRNPH2 | NM_001032393.3 | c.769T>A | p.Ser257Thr | missense_variant | 2/2 | ||
RPL36A-HNRNPH2 | NM_001199974.2 | c.*765T>A | 3_prime_UTR_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNRNPH2 | ENST00000316594.6 | c.769T>A | p.Ser257Thr | missense_variant | 2/2 | 1 | NM_019597.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 19AN: 111216Hom.: 0 Cov.: 23 AF XY: 0.000179 AC XY: 6AN XY: 33436
GnomAD3 exomes AF: 0.000169 AC: 31AN: 183504Hom.: 0 AF XY: 0.000162 AC XY: 11AN XY: 67938
GnomAD4 exome AF: 0.000347 AC: 381AN: 1097004Hom.: 0 Cov.: 31 AF XY: 0.000345 AC XY: 125AN XY: 362370
GnomAD4 genome AF: 0.000171 AC: 19AN: 111270Hom.: 0 Cov.: 23 AF XY: 0.000179 AC XY: 6AN XY: 33500
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | HNRNPH2: PP2, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The HNRNPH2 p.Ser257Thr variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs201300968) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 32 of 205159 chromosomes (11 hemizygous) at a frequency of 0.000156 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 5333 chromosomes (freq: 0.000375), European (non-Finnish) in 25 of 92650 chromosomes (freq: 0.00027) and South Asian in 5 of 19080 chromosomes (freq: 0.000262), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Ser257 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
HNRNPH2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 31, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at