17-63872184-A-C

Position:

• chr17-63872184-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020991.4(CSH2):​c.596T>G​(p.Val199Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: CSH2 NM_020991.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSH2	NM_020991.4	c.596T>G	p.Val199Gly	missense_variant	5/5	ENST00000392886.7	NP_066271.1
CSH2	NM_022645.2	c.311T>G	p.Val104Gly	missense_variant	3/3		NP_072171.1
CSH2	NM_022644.3	c.*345T>G		3_prime_UTR_variant	4/4		NP_072170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSH2	ENST00000392886.7	c.596T>G	p.Val199Gly	missense_variant	5/5	1	NM_020991.4	ENSP00000376623.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.596T>G (p.V199G) alteration is located in exon 5 (coding exon 5) of the CSH2 gene. This alteration results from a T to G substitution at nucleotide position 596, causing the valine (V) at amino acid position 199 to be replaced by a glycine (G). 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;D;D;.
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.91	D;D;D;.
M_CAP	Benign	0.0085	T
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Pathogenic	3.5	.;H;.;.
MutationTaster	Benign	0.67	D;D;D;N
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.2	D;D;D;.
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.44
MutPred		0.81		.;Loss of stability (P = 0.0178);.;.;
MVP		0.78
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.59
gMVP		0.63

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.

Other links and lift over

hg19: chr17-61949544;