Variant 17-63873262-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020991.4(CSH2):c.88G>A(p.Val30Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CSH2
NM_020991.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18

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]

CSH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10511181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CSH2	NM_020991.4 linkuse as main transcript	c.88G>A	p.Val30Ile	missense_variant	2/5	ENST00000392886.7	NP_066271.1
CSH2	NM_022644.3 linkuse as main transcript	c.88G>A	p.Val30Ile	missense_variant	2/4		NP_072170.1
CSH2	NM_022645.2 linkuse as main transcript	c.88G>A	p.Val30Ile	missense_variant	2/3		NP_072171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSH2	ENST00000392886.7 linkuse as main transcript	c.88G>A	p.Val30Ile	missense_variant	2/5	1	NM_020991.4	ENSP00000376623	P1	P0DML3-1

Frequencies

GnomAD3 genomes

AF:

0.0000919

AC:

AN:

152282

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000308

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000919

AC:

AN:

152400

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000843

Hom.:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

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

Sep 29, 2022

The c.88G>A (p.V30I) alteration is located in exon 2 (coding exon 2) of the CSH2 gene. This alteration results from a G to A substitution at nucleotide position 88, causing the valine (V) at amino acid position 30 to be replaced by an isoleucine (I). 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

0.097

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.41

CADD

Benign

6.2

DANN

Benign

0.20

DEOGEN2

Uncertain

0.43

.;T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

-0.20

N;N;N

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.21

N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.84

T;T;T

Sift4G

Benign

1.0

T;T;T

Vest4

0.17

MVP

0.12

ClinPred

0.085

GERP RS

3.4

Varity_R

0.014

gMVP

0.16

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over