rs4756846

Variant names:

• chr11-16381965-T-C
• rs4756846
• ENST00000528429.5:c.-5+20835A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145819.2(SOX6):​c.-5+20835A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0867 in 152,018 control chromosomes in the GnomAD database, including 656 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.087 (656 hom., cov: 32)
• Consequence: SOX6 NM_001145819.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 15 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145819.2. 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_001145819.2		c.-5+20835A>G		intron	N/A	NP_001139291.2	P35712-1
	SOX6	NM_033326.3		c.-4-40713A>G		intron	N/A	NP_201583.2	P35712-3
	SOX6	NM_001145811.2		c.-5+26733A>G		intron	N/A	NP_001139283.1	P35712-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX6	ENST00000528429.5	TSL:1	c.-5+20835A>G		intron	N/A	ENSP00000433233.1	P35712-1
	SOX6	ENST00000396356.7	TSL:1	c.-4-40713A>G		intron	N/A	ENSP00000379644.3	P35712-3
	SOX6	ENST00000527619.6	TSL:1	c.-5+20694A>G		intron	N/A	ENSP00000434455.2	P35712-4

Frequencies

GnomAD3 genomes AF: 0.0867 AC: 13164 AN: 151900 Hom.: 655 Cov.: 32

Gnomad AFR AF: 0.0545

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0921

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0935

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0867 AC: 13175 AN: 152018 Hom.: 656 Cov.: 32 AF XY: 0.0856 AC XY: 6363 AN XY: 74300

African (AFR) AF: 0.0546 AC: 2266 AN: 41538

American (AMR) AF: 0.0920 AC: 1404 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4824

European-Finnish (FIN) AF: 0.116 AC: 1226 AN: 10598

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7545 AN: 67844

Other (OTH) AF: 0.0925 AC: 195 AN: 2108

Alfa AF: 0.0955 Hom.: 1604

Bravo AF: 0.0818

Asia WGS AF: 0.0150 AC: 55 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.48
PhyloP100		0.037
PromoterAI		-0.00070	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4756846; hg19: chr11-16403511;