rs2229989

Variant names:

• chr17-72122794-C-G
• rs2229989
• NM_000346.4:c.507C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-72122794-C-G
• chr17-72122794-C-T
• chr17-72122794-C-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM1 PM2 PP3 PP5

The NM_000346.4(SOX9):​c.507C>G​(p.His169Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002144903: Experimental studies have shown that this missense change affects SOX9 function (PMID:24038782)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H169H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX9 NM_000346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 0.441
• Publications: 37 publications found

Genes affected

SOX9 (HGNC:11204): (SRY-box transcription factor 9) The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal. [provided by RefSeq, Jul 2008]

SOX9-AS1 (HGNC:49321): (SOX9 antisense RNA 1)

ENSG00000288605 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002144903: Experimental studies have shown that this missense change affects SOX9 function (PMID: 24038782).; SCV006582141: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product." PMID: 24038782; SCV004028115: Published functional studies suggest a damaging effect with reduced transactivation capacity of the protein (Matsushita et al., 2013); PMID:24038782; SCV001444509: Using a luciferase assay in COS7 cells transiently expressing the mutation, Matsushita et al. (2013) found significantly reduced transactivation activity of the mutant protein at 46% of WT activity. They propose that the mutant retains some residual transactivation capacity for SOX9-responsive regulatory regions, explaining why some patients have relatively mild disease.
• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000346.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant 17-72122794-C-G is Pathogenic according to our data. Variant chr17-72122794-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235914.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000346.4. 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
	SOX9	NM_000346.4	MANE Select	c.507C>G	p.His169Gln	missense	Exon 2 of 3	NP_000337.1	P48436

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX9	ENST00000245479.3	TSL:1 MANE Select	c.507C>G	p.His169Gln	missense	Exon 2 of 3	ENSP00000245479.2	P48436
	SOX9	ENST00000877559.1		c.672C>G	p.His224Gln	missense	Exon 2 of 3	ENSP00000547618.1
	SOX9-AS1	ENST00000414600.1	TSL:3	n.96+18891G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	Camptomelic dysplasia (4)
2	1	-	not provided (3)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.44
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.027	D
Polyphen		0.051	B
Vest4		0.97
MutPred		0.44		Gain of MoRF binding (P = 0.0923)
MVP		0.99
MPC		0.90
ClinPred		0.90	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs2229989; hg19: chr17-70118935;