12-23536528-T-C

Position:

• chr12-23536528-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006940.6(SOX5):​c.1913A>G​(p.Lys638Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX5 NM_006940.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SOX5
• BP4: Computational evidence support a benign effect (MetaRNN=0.4116071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX5	NM_006940.6	c.1913A>G	p.Lys638Arg	missense_variant	14/15	ENST00000451604.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX5	ENST00000451604.7	c.1913A>G	p.Lys638Arg	missense_variant	14/15	1	NM_006940.6	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 638 of the SOX5 protein (p.Lys638Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOX5-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	0.0024	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.;.;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	N;N;N;N;N;.;N;N
REVEL	Benign	0.19
Sift	Benign	0.14	T;T;T;T;T;.;T;T
Sift4G	Benign	0.17	T;T;T;T;T;.;T;T
Polyphen		0.018, 0.97, 1.0	.;B;D;.;B;B;D;.
Vest4		0.51
MutPred		0.37		.;.;Gain of catalytic residue at L640 (P = 0);.;.;.;.;.;
MVP		0.70
MPC		2.5
ClinPred		0.86	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.81

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: chr12-23689462;