17-63872867-G-A

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

Scores

5
7
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46
Variant links:
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]

Genome browser will be placed here

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
CSH2NM_020991.4 linkuse as main transcriptc.259C>T p.Pro87Ser missense_variant 3/5 ENST00000392886.7 NP_066271.1
CSH2NM_022644.3 linkuse as main transcriptc.259C>T p.Pro87Ser missense_variant 3/4 NP_072170.1
CSH2NM_022645.2 linkuse as main transcriptc.171+312C>T intron_variant NP_072171.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CSH2ENST00000392886.7 linkuse as main transcriptc.259C>T p.Pro87Ser missense_variant 3/51 NM_020991.4 ENSP00000376623 P1P0DML3-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
3
AN:
102214
Hom.:
0
Cov.:
12
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000231
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000203
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000621
AC:
4
AN:
64446
Hom.:
0
AF XY:
0.0000618
AC XY:
2
AN XY:
32362
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000242
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000481
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000214
AC:
20
AN:
933104
Hom.:
0
Cov.:
14
AF XY:
0.0000236
AC XY:
11
AN XY:
465708
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000219
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000199
Gnomad4 OTH exome
AF:
0.0000238
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000294
AC:
3
AN:
102214
Hom.:
0
Cov.:
12
AF XY:
0.0000215
AC XY:
1
AN XY:
46418
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000231
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000203
Gnomad4 OTH
AF:
0.00

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 submitterclinical testingAmbry GeneticsAug 23, 2021The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.071
D
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.;D
Eigen
Benign
0.000056
Eigen_PC
Benign
-0.062
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.79
T;T;T
M_CAP
Benign
0.028
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Uncertain
0.25
D
MutationAssessor
Pathogenic
3.6
H;H;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.36
T
PROVEAN
Pathogenic
-7.1
D;D;D
REVEL
Uncertain
0.48
Sift
Uncertain
0.011
D;D;D
Sift4G
Uncertain
0.032
D;D;D
Vest4
0.59
MutPred
0.73
Gain of phosphorylation at P87 (P = 0.0485);Gain of phosphorylation at P87 (P = 0.0485);.;
MVP
0.49
ClinPred
0.37
T
GERP RS
3.7
Varity_R
0.49
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1219707292; hg19: chr17-61950227; API