chr17-63872734-T-A

Variant names:

• chr17-63872734-T-A
• rs778807667
• NM_020991.4:c.299A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_020991.4(CSH2):​c.299A>T​(p.Glu100Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 21)
  • Exomes 𝑓: 0.0000070 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSH2 NM_020991.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92
• Publications: 0 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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.299A>T	p.Glu100Val	missense	Exon 4 of 5	NP_066271.1	P0DML3-1
	CSH2	NM_022644.3		c.299A>T	p.Glu100Val	missense	Exon 4 of 4	NP_072170.1	A6NIT4
	CSH2	NM_022645.2		c.172-411A>T		intron	N/A	NP_072171.1	B1A4H9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSH2	ENST00000392886.7	TSL:1 MANE Select	c.299A>T	p.Glu100Val	missense	Exon 4 of 5	ENSP00000376623.2	P0DML3-1
	CSH2	ENST00000613718.3	TSL:1	c.32A>T	p.Glu11Val	missense	Exon 3 of 4	ENSP00000478842.1	A0A087WUG6
	CSH2	ENST00000336844.9	TSL:2	c.299A>T	p.Glu100Val	missense	Exon 4 of 4	ENSP00000338816.5	P0DML3-2

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 14 AN: 132374 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.000345

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: 0.00

Gnomad OTH AF: 0.00116

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183218 AF XY: 0.0000302

Gnomad AFR exome AF: 0.000298

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000701 AC: 10 AN: 1426824 Hom.: 0 Cov.: 31 AF XY: 0.00000425 AC XY: 3 AN XY: 706270

African (AFR) AF: 0.000123 AC: 4 AN: 32580

American (AMR) AF: 0.00 AC: 0 AN: 39986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 38148

South Asian (SAS) AF: 0.00 AC: 0 AN: 83320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4332

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092658

Other (OTH) AF: 0.000102 AC: 6 AN: 58852

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000106 AC: 14 AN: 132374 Hom.: 1 Cov.: 21 AF XY: 0.000127 AC XY: 8 AN XY: 63238

African (AFR) AF: 0.000345 AC: 12 AN: 34800

American (AMR) AF: 0.00 AC: 0 AN: 12692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3304

East Asian (EAS) AF: 0.00 AC: 0 AN: 4598

South Asian (SAS) AF: 0.00 AC: 0 AN: 3532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62128

Other (OTH) AF: 0.00116 AC: 2 AN: 1728

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000174 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	0.17
Eigen_PC	Benign	-0.0059
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		3.9
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.75
MutPred		0.68		Loss of disorder (P = 0.0101)
MVP		0.78
ClinPred		0.97	D
GERP RS		2.7
Varity_R		0.76
gMVP		0.42

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

Other links and lift over

dbSNP: rs778807667; hg19: chr17-61950094;