12-23534518-G-C

Position:

• chr12-23534518-G-C

Variant summary

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

The NM_006940.6(SOX5):​c.1993C>G​(p.Gln665Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SOX5 NM_006940.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.03

Genes affected

SOX5 (HGNC:11201): (SRY-box transcription factor 5) This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. The encoded protein may play a role in chondrogenesis. A pseudogene of this gene is located on chromosome 8. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

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), SOX5. . Gene score misZ 3.1513 (greater than the threshold 3.09). Trascript score misZ 3.799 (greater than threshold 3.09). GenCC has associacion of gene with Lamb-Shaffer syndrome, developmental and speech delay due to SOX5 deficiency.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX5	NM_006940.6	c.1993C>G	p.Gln665Glu	missense_variant	15/15	ENST00000451604.7	NP_008871.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX5	ENST00000451604.7	c.1993C>G	p.Gln665Glu	missense_variant	15/15	1	NM_006940.6	ENSP00000398273	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;.;T;T;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;.;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.6	.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N;N;N;N;N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.037	D;D;D;D;D;.;T;D
Sift4G	Benign	0.60	T;T;T;T;T;.;T;T
Polyphen		0.81, 0.94, 0.95	.;P;P;.;P;P;P;.
Vest4		0.43
MutPred		0.40		.;.;Gain of catalytic residue at I668 (P = 0.0107);.;.;.;.;.;
MVP		0.33
MPC		0.43
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.36
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-23687452;