11-15973029-G-C

Position:

• chr11-15973029-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001367873.1(SOX6):​c.2267C>G​(p.Pro756Arg) variant causes a missense change involving the alteration of a 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SOX6 NM_001367873.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.60

Genes affected

SOX6 (HGNC:16421): (SRY-box transcription factor 6) This gene encodes a member of the D subfamily of sex determining region y-related transcription factors that are characterized by a conserved DNA-binding domain termed the high mobility group box and by their ability to bind the minor groove of DNA. The encoded protein is a transcriptional activator that is required for normal development of the central nervous system, chondrogenesis and maintenance of cardiac and skeletal muscle cells. The encoded protein interacts with other family members to cooperatively activate gene expression. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SOX6. . Gene score misZ 1.9285 (greater than the threshold 3.09). Trascript score misZ 3.2843 (greater than threshold 3.09). GenCC has associacion of gene with Tolchin-Le Caignec syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX6	NM_001367873.1	c.2267C>G	p.Pro756Arg	missense_variant	16/16	ENST00000683767.1	NP_001354802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX6	ENST00000683767.1	c.2267C>G	p.Pro756Arg	missense_variant	16/16		NM_001367873.1	ENSP00000507545	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SOX6-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

The SOX6 c.2306C>G variant is predicted to result in the amino acid substitution p.Pro769Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;.;.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.0	D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.82
MutPred		0.19		.;.;.;.;Loss of glycosylation at T753 (P = 0.0586);
MVP		0.79
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs1326972429; hg19: chr11-15994575;