17-63872686-A-C

Variant names:

• chr17-63872686-A-C
• NM_020991.4:c.347T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020991.4(CSH2):​c.347T>G​(p.Val116Gly) variant causes a missense change. 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: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSH2 NM_020991.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSH2	NM_020991.4	c.347T>G	p.Val116Gly	missense_variant	Exon 4 of 5	ENST00000392886.7	NP_066271.1
CSH2	NM_022644.3	c.347T>G	p.Val116Gly	missense_variant	Exon 4 of 4		NP_072170.1
CSH2	NM_022645.2	c.172-363T>G		intron_variant	Intron 2 of 2		NP_072171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSH2	ENST00000392886.7	c.347T>G	p.Val116Gly	missense_variant	Exon 4 of 5	1	NM_020991.4	ENSP00000376623.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1458020 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725102

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: 0.00

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.347T>G (p.V116G) alteration is located in exon 4 (coding exon 4) of the CSH2 gene. This alteration results from a T to G substitution at nucleotide position 347, causing the valine (V) at amino acid position 116 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	Benign	0.24
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;D;.
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.51	T;T;T;.
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-5.8	D;D;D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Vest4		0.64
MutPred		0.81		Loss of stability (P = 0.0215);Loss of stability (P = 0.0215);.;.;
MVP		0.89
ClinPred		0.91	D
GERP RS		2.7
Varity_R		0.48
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-61950046;