rs199750760

Positions:

• chr22-37983663-C-A
• chr22-37983663-C-T

Variant summary

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

The NM_006941.4(SOX10):​c.122G>T​(p.Gly41Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,584,728 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.83

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]

SOX10 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0086992085).
• BP6: Variant 22-37983663-C-A is Benign according to our data. Variant chr22-37983663-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 341622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37983663-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000401 (61/152144) while in subpopulation EAS AF= 0.0093 (48/5160). AF 95% confidence interval is 0.00721. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX10	NM_006941.4	c.122G>T	p.Gly41Val	missense_variant	2/4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-2491C>A		intron_variant			NP_001288059.1
POLR2F	NM_001363825.1	c.*38+11353C>A		intron_variant			NP_001350754.1
POLR2F	NM_001301131.2	c.293+16493C>A		intron_variant			NP_001288060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.122G>T	p.Gly41Val	missense_variant	2/4	1	NM_006941.4	ENSP00000380093.2

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00927

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000575 AC: 116 AN: 201896 Hom.: 1 AF XY: 0.000576 AC XY: 64 AN XY: 111200

Gnomad AFR exome AF: 0.000163

Gnomad AMR exome AF: 0.0000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00710

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000384

GnomAD4 exome AF: 0.000232 AC: 332 AN: 1432584 Hom.: 1 Cov.: 32 AF XY: 0.000233 AC XY: 166 AN XY: 711482

Gnomad4 AFR exome AF: 0.0000910

Gnomad4 AMR exome AF: 0.0000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00652

Gnomad4 SAS exome AF: 0.0000357

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74382

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00930

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000450

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000450 AC: 52

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2019	This variant is associated with the following publications: (PMID: 22008330, 30914325, 30936914) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 22, 2016

p.Gly41Val in exon 2 of SOX10: This variant is not expected to have clinical sig nificance because it has been identified in 0.71% (118/4634) of East Asian chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs199750760). Additionally, this variant was reported as a polymorphi sm in a case-control study on Hirschsprung disease in the Han Chinese population (Pan 2011). -

PCWH syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Waardenburg syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D;D;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.50	.;T;T
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.059	T;T;D
Sift4G	Uncertain	0.013	D;D;.
Polyphen		0.085	B;B;.
Vest4		0.20
MVP		0.65
MPC		1.0
ClinPred		0.016	T
GERP RS		3.3
Varity_R		0.17
gMVP		0.66

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

Other links and lift over

dbSNP: rs199750760; hg19: chr22-38379670;