17-63872302-G-A

Position:

• chr17-63872302-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020991.4(CSH2):​c.478C>T​(p.Arg160Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: CSH2 NM_020991.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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 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=0.09272078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSH2	NM_020991.4	c.478C>T	p.Arg160Trp	missense_variant	5/5	ENST00000392886.7	NP_066271.1
CSH2	NM_022645.2	c.193C>T	p.Arg65Trp	missense_variant	3/3		NP_072171.1
CSH2	NM_022644.3	c.*227C>T		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.478C>T	p.Arg160Trp	missense_variant	5/5	1	NM_020991.4	ENSP00000376623	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152150 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 28 AN: 250872 Hom.: 1 AF XY: 0.0000885 AC XY: 12 AN XY: 135650

Gnomad AFR exome AF: 0.000933

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461614 Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34 AN XY: 727120

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152268 Hom.: 0 Cov.: 29 AF XY: 0.000255 AC XY: 19 AN XY: 74450

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000355

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

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 07, 2022

The c.478C>T (p.R160W) alteration is located in exon 5 (coding exon 5) of the CSH2 gene. This alteration results from a C to T substitution at nucleotide position 478, causing the arginine (R) at amino acid position 160 to be replaced by a tryptophan (W). 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	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Uncertain	0.78	.;D;D;.
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D;D;D;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.6	.;M;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.0	D;D;D;.
REVEL	Uncertain	0.46
Sift	Benign	0.039	D;D;D;.
Sift4G	Benign	0.071	T;T;T;T
Vest4		0.41
MVP		0.73
ClinPred		0.061	T
GERP RS		2.9
Varity_R		0.089
gMVP		0.47

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

Other links and lift over

dbSNP: rs184890744; hg19: chr17-61949662;