Variant 17-63872659-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_020991.4(CSH2):c.374A>G(p.Asn125Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,609,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 28)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CSH2
NM_020991.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.91

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 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
CSH2	NM_020991.4 link	c.374A>G	p.Asn125Ser	missense_variant	Exon 4 of 5	ENST00000392886.7	NP_066271.1	P0DML3-1A0A0M6L0F6
CSH2	NM_022644.3 link	c.374A>G	p.Asn125Ser	missense_variant	Exon 4 of 4		NP_072170.1	A6NIT4
CSH2	NM_022645.2 link	c.172-336A>G		intron_variant	Intron 2 of 2		NP_072171.1	B1A4H9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSH2	ENST00000392886.7 link	c.374A>G	p.Asn125Ser	missense_variant	Exon 4 of 5	1	NM_020991.4	ENSP00000376623.2		P0DML3-1

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147836

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000680

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461466

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147954

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72002

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000679

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374A>G (p.N125S) alteration is located in exon 4 (coding exon 4) of the CSH2 gene. This alteration results from a A to G substitution at nucleotide position 374, causing the asparagine (N) at amino acid position 125 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

Benign

0.079

BayesDel_addAF

Benign

0.0085

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.77

D;.;D;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

D;D;D;.

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.67

D;D;D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.2

M;M;.;.

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.9

D;D;D;.

REVEL

Uncertain

0.59

Sift

Benign

0.061

T;D;T;.

Sift4G

Benign

0.067

T;T;T;T

Vest4

0.34

MutPred

0.76

Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);.;.;

MVP

0.55

ClinPred

0.85

GERP RS

3.8

Varity_R

0.24

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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