Genetic Variant CSH2:p.Ser214Asn (chr17-63872139-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020991.4(CSH2):c.641G>A(p.Ser214Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CSH2
NM_020991.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.93

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2600611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSH2	NM_020991.4 link	c.641G>A	p.Ser214Asn	missense_variant	Exon 5 of 5	ENST00000392886.7	NP_066271.1	P0DML3-1A0A0M6L0F6
CSH2	NM_022645.2 link	c.356G>A	p.Ser119Asn	missense_variant	Exon 3 of 3		NP_072171.1	B1A4H9
CSH2	NM_022644.3 link	c.*390G>A		3_prime_UTR_variant	Exon 4 of 4		NP_072170.1	A6NIT4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSH2	ENST00000392886.7 link	c.641G>A	p.Ser214Asn	missense_variant	Exon 5 of 5	1	NM_020991.4	ENSP00000376623.2		P0DML3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727216

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Uncertain

0.44

.;T;T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.81

T;T;T;.

M_CAP

Benign

0.038

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.80

.;N;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.82

N;N;N;.

REVEL

Benign

0.28

Sift

Benign

0.093

T;T;T;.

Sift4G

Benign

0.25

T;T;T;T

Vest4

0.10

MutPred

0.50

.;Loss of disorder (P = 0.0855);.;.;

MVP

0.43

ClinPred

0.55

GERP RS

1.9

Varity_R

0.10

gMVP

0.23

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over