rs561223596

Variant names:

• chr17-63872165-C-G
• rs561223596
• NM_020991.4:c.615G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-63872165-C-G
• chr17-63872165-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_020991.4(CSH2):​c.615G>C​(p.Met205Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CSH2 NM_020991.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.578
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08827534).
• BP6: Variant 17-63872165-C-G is Benign according to our data. Variant chr17-63872165-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3269769.Status of the report is criteria_provided_single_submitter, 1 stars.

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.615G>C	p.Met205Ile	missense	Exon 5 of 5	NP_066271.1	P0DML3-1
	CSH2	NM_022645.2		c.330G>C	p.Met110Ile	missense	Exon 3 of 3	NP_072171.1	B1A4H9
	CSH2	NM_022644.3		c.*364G>C		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.615G>C	p.Met205Ile	missense	Exon 5 of 5	ENSP00000376623.2	P0DML3-1
	CSH2	ENST00000613718.3	TSL:1	c.348G>C	p.Met116Ile	missense	Exon 4 of 4	ENSP00000478842.1	A0A087WUG6
	CSH2	ENST00000560142.5	TSL:5	c.444G>C	p.Met148Ile	missense	Exon 5 of 5	ENSP00000453452.1	H0YM39

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251480 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 AF: 0.0000185 AC: 27 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727216

African (AFR) AF: 0.0000299 AC: 1 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: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 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: 0.0000180 AC: 20 AN: 1111948

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

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	0.21
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	1.6
DANN	Benign	0.57
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.97	N
PhyloP100		0.58
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.86	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.16
MutPred		0.53		Loss of phosphorylation at T201 (P = 0.1636)
MVP		0.092
ClinPred		0.037	T
GERP RS		-2.3
Varity_R		0.18
gMVP		0.26
Mutation Taster		=99/1	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: rs561223596; hg19: chr17-61949525;