chr22-37973969-A-G

Variant names:

• chr22-37973969-A-G
• rs139884
• NM_006941.4:c.927T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006941.4(SOX10):​c.927T>C​(p.His309His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,611,716 control chromosomes in the GnomAD database, including 336,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36393 hom., cov: 34)
  • Exomes 𝑓: 0.64 (300081 hom.)
• Consequence: SOX10 NM_006941.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.28
• Publications: 39 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-37973969-A-G is Benign according to our data. Variant chr22-37973969-A-G is described in ClinVar as Benign. ClinVar VariationId is 227081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	NM_006941.4	MANE Select	c.927T>C	p.His309His	synonymous	Exon 4 of 4	NP_008872.1	P56693-1
	POLR2F	NM_001301130.2		c.293+6799A>G		intron	N/A	NP_001288059.1	B0QYL9
	POLR2F	NM_001363825.1		c.*38+1659A>G		intron	N/A	NP_001350754.1	F8WC47

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	ENST00000396884.8	TSL:1 MANE Select	c.927T>C	p.His309His	synonymous	Exon 4 of 4	ENSP00000380093.2	P56693-1
	SOX10	ENST00000360880.6	TSL:1	c.927T>C	p.His309His	synonymous	Exon 5 of 5	ENSP00000354130.2	P56693-1
	SOX10	ENST00000698177.1		c.1143T>C	p.His381His	synonymous	Exon 5 of 5	ENSP00000513596.1	A0A8V8TM01

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104187 AN: 152088 Hom.: 36348 Cov.: 34

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.657

GnomAD2 exomes AF: 0.650 AC: 161930 AN: 249110 AF XY: 0.645

Gnomad AFR exome AF: 0.826

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.760

Gnomad FIN exome AF: 0.628

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.637

GnomAD4 exome AF: 0.639 AC: 933210 AN: 1459510 Hom.: 300081 Cov.: 63 AF XY: 0.638 AC XY: 463571 AN XY: 726180

African (AFR) AF: 0.829 AC: 27760 AN: 33478

American (AMR) AF: 0.626 AC: 28003 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15702 AN: 26134

East Asian (EAS) AF: 0.728 AC: 28890 AN: 39700

South Asian (SAS) AF: 0.632 AC: 54546 AN: 86254

European-Finnish (FIN) AF: 0.627 AC: 32116 AN: 51242

Middle Eastern (MID) AF: 0.652 AC: 3757 AN: 5762

European-Non Finnish (NFE) AF: 0.632 AC: 703023 AN: 1111864

Other (OTH) AF: 0.653 AC: 39413 AN: 60360

GnomAD4 genome AF: 0.685 AC: 104298 AN: 152206 Hom.: 36393 Cov.: 34 AF XY: 0.682 AC XY: 50722 AN XY: 74406

African (AFR) AF: 0.823 AC: 34181 AN: 41532

American (AMR) AF: 0.640 AC: 9787 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2073 AN: 3470

East Asian (EAS) AF: 0.757 AC: 3916 AN: 5174

South Asian (SAS) AF: 0.624 AC: 3006 AN: 4820

European-Finnish (FIN) AF: 0.615 AC: 6520 AN: 10596

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42739 AN: 68004

Other (OTH) AF: 0.655 AC: 1383 AN: 2112

Alfa AF: 0.641 Hom.: 41759

Bravo AF: 0.694

Asia WGS AF: 0.682 AC: 2376 AN: 3478

EpiCase AF: 0.624

EpiControl AF: 0.621

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	2	PCWH syndrome (2)
-	-	1	Waardenburg syndrome (1)
-	-	1	Waardenburg syndrome type 2E (1)
-	-	1	Waardenburg syndrome type 4C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.080
DANN	Benign	0.47
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs139884; hg19: chr22-38369976; COSMIC: COSV62807092; COSMIC: COSV62807092;