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GeneBe

22-37974143-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_006941.4(SOX10):c.753G>A(p.Ser251=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,611,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S251S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

SOX10
NM_006941.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.272
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 22-37974143-C-T is Benign according to our data. Variant chr22-37974143-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 341617.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=3}.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.272 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000335 (51/152024) while in subpopulation EAS AF= 0.00193 (10/5174). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOX10NM_006941.4 linkuse as main transcriptc.753G>A p.Ser251= synonymous_variant 4/4 ENST00000396884.8
POLR2FNM_001301130.2 linkuse as main transcriptc.293+6973C>T intron_variant
POLR2FNM_001301131.2 linkuse as main transcriptc.293+6973C>T intron_variant
POLR2FNM_001363825.1 linkuse as main transcriptc.*38+1833C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOX10ENST00000396884.8 linkuse as main transcriptc.753G>A p.Ser251= synonymous_variant 4/41 NM_006941.4 P1P56693-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000335
AC:
51
AN:
152024
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00193
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000368
Gnomad OTH
AF:
0.000960
GnomAD3 exomes
AF:
0.000557
AC:
137
AN:
246080
Hom.:
0
AF XY:
0.000546
AC XY:
73
AN XY:
133678
show subpopulations
Gnomad AFR exome
AF:
0.000124
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00149
Gnomad EAS exome
AF:
0.00294
Gnomad SAS exome
AF:
0.000555
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000423
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000404
AC:
590
AN:
1459224
Hom.:
0
Cov.:
40
AF XY:
0.000419
AC XY:
304
AN XY:
726084
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00187
Gnomad4 EAS exome
AF:
0.00116
Gnomad4 SAS exome
AF:
0.000661
Gnomad4 FIN exome
AF:
0.0000197
Gnomad4 NFE exome
AF:
0.000368
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000335
AC:
51
AN:
152024
Hom.:
0
Cov.:
32
AF XY:
0.000350
AC XY:
26
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00193
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.000368
Gnomad4 OTH
AF:
0.000960
Alfa
AF:
0.000189
Hom.:
0
Bravo
AF:
0.000374
EpiCase
AF:
0.000545
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2023SOX10: BP4, BP7 -
Benign, criteria provided, single submitterclinical testingInvitaeNov 07, 2023- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 28, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 21, 2017- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 20, 2017p.Ser251Ser in exon 4 of SOX10: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. This variant has been identified in 0.1% (13 /10124) of Ashkenazi Jewish chromosomes and 0.3% (59/18832) of East Asian chromo somes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.o rg; dbSNP rs376907937). -
PCWH syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Waardenburg syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.39
Cadd
Benign
9.1
Dann
Benign
0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376907937; hg19: chr22-38370150; API