22-37983658-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_Supporting

The NM_006941.4(SOX10):​c.127C>G​(p.Arg43Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,438,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000035 ( 0 hom. )

Consequence

SOX10
NM_006941.4 missense

Scores

2
2
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.10
Variant links:
Genes affected
SOX10 (HGNC:11190): (SRY-box transcription factor 10) 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 activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development. Mutations in this gene are associated with Waardenburg-Shah and Waardenburg-Hirschsprung disease. [provided by RefSeq, Jul 2008]
POLR2F (HGNC:9193): (RNA polymerase II, I and III subunit F) This gene encodes the sixth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. In yeast, this polymerase subunit, in combination with at least two other subunits, forms a structure that stabilizes the transcribing polymerase on the DNA template. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25322062).
BS2
High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SOX10NM_006941.4 linkc.127C>G p.Arg43Gly missense_variant Exon 2 of 4 ENST00000396884.8 NP_008872.1 P56693-1A0A024R1N6
POLR2FNM_001301130.2 linkc.294-2496G>C intron_variant Intron 4 of 5 NP_001288059.1 B0QYL9
POLR2FNM_001363825.1 linkc.*38+11348G>C intron_variant Intron 5 of 5 NP_001350754.1
POLR2FNM_001301131.2 linkc.293+16488G>C intron_variant Intron 4 of 4 NP_001288060.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SOX10ENST00000396884.8 linkc.127C>G p.Arg43Gly missense_variant Exon 2 of 4 1 NM_006941.4 ENSP00000380093.2 P56693-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000348
AC:
5
AN:
1438594
Hom.:
0
Cov.:
32
AF XY:
0.00000420
AC XY:
3
AN XY:
715000
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000452
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
0.063
BayesDel_addAF
Benign
-0.045
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
17
DANN
Benign
0.94
DEOGEN2
Uncertain
0.50
D;D;T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.26
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.60
.;T;T
M_CAP
Pathogenic
0.48
D
MetaRNN
Benign
0.25
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.8
L;L;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-1.1
N;N;N
REVEL
Benign
0.15
Sift
Benign
0.38
T;T;T
Sift4G
Benign
0.38
T;T;.
Polyphen
0.0070
B;B;.
Vest4
0.20
MutPred
0.26
Loss of methylation at R43 (P = 0.0384);Loss of methylation at R43 (P = 0.0384);Loss of methylation at R43 (P = 0.0384);
MVP
0.76
MPC
1.1
ClinPred
0.10
T
GERP RS
3.3
Varity_R
0.18
gMVP
0.43

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: chr22-38379665; API