17-63909818-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022579.3(CSHL1):​c.562C>T​(p.Leu188Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CSHL1
NM_022579.3 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24
Variant links:
Genes affected
CSHL1 (HGNC:2442): (chorionic somatomammotropin hormone like 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed 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. This particular family member is expressed in placental villi, although it was originally thought to be a pseudogene. In fact, alternative splicing suggests that the majority of the transcripts would be unable to express a secreted protein. Alternatively spliced transcript variants encoding different isoforms have been identified. [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.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CSHL1NM_022579.3 linkc.562C>T p.Leu188Phe missense_variant Exon 5 of 5 ENST00000309894.6 NP_072101.1 Q14406-1I6L999

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CSHL1ENST00000309894.6 linkc.562C>T p.Leu188Phe missense_variant Exon 5 of 5 5 NM_022579.3 ENSP00000309524.5 Q14406-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251284
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135800
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461704
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727154
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.562C>T (p.L188F) alteration is located in exon 5 (coding exon 5) of the CSHL1 gene. This alteration results from a C to T substitution at nucleotide position 562, causing the leucine (L) at amino acid position 188 to be replaced by a phenylalanine (F). 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
Benign
0.15
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.24
.;.;.;.;T
Eigen
Benign
-0.0099
Eigen_PC
Benign
-0.070
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.84
T;T;T;T;T
M_CAP
Benign
0.059
D
MetaRNN
Uncertain
0.68
D;D;D;D;D
MetaSVM
Uncertain
0.092
D
MutationAssessor
Benign
1.8
.;.;.;.;L
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.5
N;.;N;N;N
REVEL
Uncertain
0.60
Sift
Benign
0.055
T;.;T;T;T
Sift4G
Benign
0.090
T;T;T;T;T
Polyphen
0.89, 0.56
.;.;P;P;P
Vest4
0.49
MutPred
0.56
.;.;.;.;Gain of catalytic residue at L188 (P = 0.045);
MVP
0.82
MPC
0.20
ClinPred
0.41
T
GERP RS
2.5
Varity_R
0.20
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
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

Publications

LitVar

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

Other links and lift over

dbSNP: rs369769197; hg19: chr17-61987178; API