NM_001367873.1:c.2245A>G

Variant names:

• chr11-15973051-T-C
• NM_001367873.1:c.2245A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001367873.1(SOX6):​c.2245A>G​(p.Met749Val) 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: 7.67
• Publications: 0 publications found

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]

SOX6 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Tolchin-Le Caignec syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367873.1. 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
	SOX6	NM_001367873.1	MANE Select	c.2245A>G	p.Met749Val	missense	Exon 16 of 16	NP_001354802.1	P35712-1
	SOX6	NM_001145819.2		c.2245A>G	p.Met749Val	missense	Exon 16 of 16	NP_001139291.2	P35712-1
	SOX6	NM_033326.3		c.2185A>G	p.Met729Val	missense	Exon 16 of 16	NP_201583.2	P35712-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX6	ENST00000683767.1	MANE Select	c.2245A>G	p.Met749Val	missense	Exon 16 of 16	ENSP00000507545.1	P35712-1
	SOX6	ENST00000528429.5	TSL:1	c.2245A>G	p.Met749Val	missense	Exon 16 of 16	ENSP00000433233.1	P35712-1
	SOX6	ENST00000396356.7	TSL:1	c.2185A>G	p.Met729Val	missense	Exon 16 of 16	ENSP00000379644.3	P35712-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.31
Sift	Benign	0.077	T
Sift4G	Benign	0.13	T
Polyphen		0.71	P
Vest4		0.78
MutPred		0.32		Gain of catalytic residue at M749 (P = 0.0063)
MVP		0.82
MPC		1.9
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.62
Mutation Taster		=10/90	disease causing

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

hg19: chr11-15994597;