17-63872867-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_020991.4(CSH2):c.259C>T(p.Pro87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000029 ( 0 hom., cov: 12)
Exomes 𝑓: 0.000021 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CSH2
NM_020991.4 missense
NM_020991.4 missense
Scores
5
7
7
Clinical Significance
Conservation
PhyloP100: 2.46
Genes affected
CSH2 (HGNC:2441): (chorionic somatomammotropin hormone 2) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones and plays an important role in growth control. The gene is located at the growth hormone locus on chromosome 17 along with four other related genes in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. Although the five genes share a remarkably high degree of sequence identity, they are expressed selectively in different tissues. Alternative splicing generates additional isoforms of each of the five growth hormones. This particular family member is expressed mainly in the placenta and utilizes multiple transcription initiation sites. Expression of the identical mature proteins for chorionic somatomammotropin hormones 1 and 2 is upregulated during development, while the ratio of 1 to 2 increases by term. Structural and expression differences provide avenues for developmental regulation and tissue specificity. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.841
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CSH2 | NM_020991.4 | c.259C>T | p.Pro87Ser | missense_variant | 3/5 | ENST00000392886.7 | NP_066271.1 | |
CSH2 | NM_022644.3 | c.259C>T | p.Pro87Ser | missense_variant | 3/4 | NP_072170.1 | ||
CSH2 | NM_022645.2 | c.171+312C>T | intron_variant | NP_072171.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CSH2 | ENST00000392886.7 | c.259C>T | p.Pro87Ser | missense_variant | 3/5 | 1 | NM_020991.4 | ENSP00000376623 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 3AN: 102214Hom.: 0 Cov.: 12 FAILED QC
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GnomAD3 exomes AF: 0.0000621 AC: 4AN: 64446Hom.: 0 AF XY: 0.0000618 AC XY: 2AN XY: 32362
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000214 AC: 20AN: 933104Hom.: 0 Cov.: 14 AF XY: 0.0000236 AC XY: 11AN XY: 465708
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000294 AC: 3AN: 102214Hom.: 0 Cov.: 12 AF XY: 0.0000215 AC XY: 1AN XY: 46418
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2021 | The c.259C>T (p.P87S) alteration is located in exon 3 (coding exon 3) of the CSH2 gene. This alteration results from a C to T substitution at nucleotide position 259, causing the proline (P) at amino acid position 87 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Vest4
MutPred
Gain of phosphorylation at P87 (P = 0.0485);Gain of phosphorylation at P87 (P = 0.0485);.;
MVP
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at