11-15972990-G-C

Position:

• chr11-15972990-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001367873.1(SOX6):​c.2306C>G​(p.Pro769Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX6 NM_001367873.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter 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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX6	NM_001367873.1	c.2306C>G	p.Pro769Arg	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.2306C>G	p.Pro769Arg	missense_variant	16/16		NM_001367873.1	ENSP00000507545	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

The c.2246C>G (p.P749R) alteration is located in exon 16 (coding exon 15) of the SOX6 gene. This alteration results from a C to G substitution at nucleotide position 2246, causing the proline (P) at amino acid position 749 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;.;.;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	D;D;.;D;P
Vest4		0.74
MutPred		0.28		.;.;.;.;Loss of glycosylation at P769 (P = 0.0151);
MVP		0.75
MPC		2.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.67
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-15994536;