NM_006941.4:c.482_483insGCTCCT

Variant names:

• chr22-37978081-A-AAGGAGC
• rs397515366
• NM_006941.4:c.482_483insGCTCCT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_006941.4(SOX10):​c.482_483insGCTCCT​(p.Arg161_Met162insLeuLeu) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX10 NM_006941.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006941.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006941.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 22-37978081-A-AAGGAGC is Pathogenic according to our data. Variant chr22-37978081-A-AAGGAGC is described in ClinVar as Pathogenic. ClinVar VariationId is 7395.Status of the report is no_assertion_criteria_provided, 0 stars.

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.482_483insGCTCCT	p.Arg161_Met162insLeuLeu	disruptive_inframe_insertion	Exon 3 of 4	NP_008872.1	P56693-1
	POLR2F	NM_001301130.2		c.294-8073_294-8072insAGGAGC		intron	N/A	NP_001288059.1	B0QYL9
	POLR2F	NM_001363825.1		c.*38+5771_*38+5772insAGGAGC		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.482_483insGCTCCT	p.Arg161_Met162insLeuLeu	disruptive_inframe_insertion	Exon 3 of 4	ENSP00000380093.2	P56693-1
	SOX10	ENST00000360880.6	TSL:1	c.482_483insGCTCCT	p.Arg161_Met162insLeuLeu	disruptive_inframe_insertion	Exon 4 of 5	ENSP00000354130.2	P56693-1
	SOX10	ENST00000698177.1		c.698_699insGCTCCT	p.Arg233_Met234insLeuLeu	disruptive_inframe_insertion	Exon 4 of 5	ENSP00000513596.1	A0A8V8TM01

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Waardenburg syndrome type 4C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=64/36	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397515366; hg19: chr22-38374088;