NM_020991.4:c.611G>T

Variant names:

• chr17-63872169-C-A
• rs377538456
• NM_020991.4:c.611G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020991.4(CSH2):​c.611G>T​(p.Arg204Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CSH2 NM_020991.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020991.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSH2	NM_020991.4	MANE Select	c.611G>T	p.Arg204Leu	missense	Exon 5 of 5	NP_066271.1	P0DML3-1
	CSH2	NM_022645.2		c.326G>T	p.Arg109Leu	missense	Exon 3 of 3	NP_072171.1	B1A4H9
	CSH2	NM_022644.3		c.*360G>T		3_prime_UTR	Exon 4 of 4	NP_072170.1	A6NIT4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSH2	ENST00000392886.7	TSL:1 MANE Select	c.611G>T	p.Arg204Leu	missense	Exon 5 of 5	ENSP00000376623.2	P0DML3-1
	CSH2	ENST00000613718.3	TSL:1	c.344G>T	p.Arg115Leu	missense	Exon 4 of 4	ENSP00000478842.1	A0A087WUG6
	CSH2	ENST00000560142.5	TSL:5	c.440G>T	p.Arg147Leu	missense	Exon 5 of 5	ENSP00000453452.1	H0YM39

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111952

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.017
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.0094	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.9
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Vest4		0.56
MutPred		0.55		Loss of MoRF binding (P = 0.0858)
MVP		0.81
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.54
gMVP		0.54
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs377538456; hg19: chr17-61949529;