11-15986197-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001367873.1(SOX6):c.2183+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,613,764 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 32)
  • Exomes 𝑓: 0.016 (215 hom.)
• Consequence: SOX6 NM_001367873.1 splice_region, intron
• Scores: Splicing: ADA: 0.00004457
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.359

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-15986197-T-C is Benign according to our data. Variant chr11-15986197-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1189992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-15986197-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1805/152282) while in subpopulation NFE AF= 0.0186 (1264/68010). AF 95% confidence interval is 0.0177. There are 15 homozygotes in gnomad4. There are 800 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1808 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX6	NM_001367873.1	c.2183+7A>G		splice_region_variant, intron_variant		ENST00000683767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX6	ENST00000683767.1	c.2183+7A>G		splice_region_variant, intron_variant			NM_001367873.1	A2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1808 AN: 152164 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00830

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0114 AC: 2862 AN: 251030 Hom.: 26 AF XY: 0.0112 AC XY: 1516 AN XY: 135750

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.00983

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0158 AC: 23141 AN: 1461482 Hom.: 215 Cov.: 31 AF XY: 0.0153 AC XY: 11129 AN XY: 727080

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.00877

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0119 AC: 1805 AN: 152282 Hom.: 15 Cov.: 32 AF XY: 0.0107 AC XY: 800 AN XY: 74464

Gnomad4 AFR AF: 0.00394

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00830

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0151 Hom.: 9

Bravo AF: 0.0122

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2020	- -

SOX6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	8.4
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.030		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: rs146661971; hg19: chr11-16007743;