NM_020991.4:c.17G>A

Variant names:

• chr17-63873333-C-T
• rs569109978
• NM_020991.4:c.17G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_020991.4(CSH2):​c.17G>A​(p.Arg6Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSH2 NM_020991.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.634

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013251126).
• BP6: Variant 17-63873333-C-T is Benign according to our data. Variant chr17-63873333-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2466750.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSH2	NM_020991.4	c.17G>A	p.Arg6Gln	missense_variant	Exon 2 of 5	ENST00000392886.7	NP_066271.1
CSH2	NM_022644.3	c.17G>A	p.Arg6Gln	missense_variant	Exon 2 of 4		NP_072170.1
CSH2	NM_022645.2	c.17G>A	p.Arg6Gln	missense_variant	Exon 2 of 3		NP_072171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSH2	ENST00000392886.7	c.17G>A	p.Arg6Gln	missense_variant	Exon 2 of 5	1	NM_020991.4	ENSP00000376623.2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152110 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000107 AC: 156 AN: 1461328 Hom.: 0 Cov.: 32 AF XY: 0.000143 AC XY: 104 AN XY: 726944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000985 AC: 15 AN: 152222 Hom.: 0 Cov.: 26 AF XY: 0.0000672 AC XY: 5 AN XY: 74420

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

ExAC AF: 0.000223 AC: 27

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 14, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	2.5
DANN	Benign	0.81
DEOGEN2	Benign	0.26	.;T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.1	L;L;L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Vest4		0.12
MVP		0.061
ClinPred		0.019	T
GERP RS		-5.2
Varity_R		0.027
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs569109978; hg19: chr17-61950693; COSMIC: COSV61080747;