chr17-63872169-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_020991.4(CSH2):​c.611G>A​(p.Arg204His) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,613,954 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000034 (2 hom.)
• Consequence: CSH2 NM_020991.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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>A	p.Arg204His	missense	Exon 5 of 5	NP_066271.1	P0DML3-1
	CSH2	NM_022645.2		c.326G>A	p.Arg109His	missense	Exon 3 of 3	NP_072171.1	B1A4H9
	CSH2	NM_022644.3		c.*360G>A		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>A	p.Arg204His	missense	Exon 5 of 5	ENSP00000376623.2	P0DML3-1
	CSH2	ENST00000613718.3	TSL:1	c.344G>A	p.Arg115His	missense	Exon 4 of 4	ENSP00000478842.1	A0A087WUG6
	CSH2	ENST00000560142.5	TSL:5	c.440G>A	p.Arg147His	missense	Exon 5 of 5	ENSP00000453452.1	H0YM39

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251478 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461828 Hom.: 2 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727218

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 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: 0.0000315 AC: 35 AN: 1111952

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 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: 0.0000294 AC: 2 AN: 68012

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

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	Benign	0.11
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.9
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.41
Sift	Benign	0.065	T
Sift4G	Benign	0.074	T
Vest4		0.64
MVP		0.70
ClinPred		0.57	D
GERP RS		3.0
Varity_R		0.11
gMVP		0.40
Mutation Taster		=81/19	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; COSMIC: COSV61081357;