rs397515502

Variant names:

• chr2-44942799-ACCCCAGCAAG-A
• rs397515502
• NM_005413.4:c.696_705delCCCCAGCAAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005413.4(SIX3):​c.696_705delCCCCAGCAAG​(p.Asn232LysfsTer16) variant causes a frameshift 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). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX3 NM_005413.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.01
• Publications: 1 publications found

Genes affected

SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

ENSG00000225156 (HGNC:):

SIX3-AS1 (HGNC:40532): (SIX3 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-44942799-ACCCCAGCAAG-A is Pathogenic according to our data. Variant chr2-44942799-ACCCCAGCAAG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 65501.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX3	NM_005413.4	c.696_705delCCCCAGCAAG	p.Asn232LysfsTer16	frameshift_variant	Exon 1 of 2	ENST00000260653.5	NP_005404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX3	ENST00000260653.5	c.696_705delCCCCAGCAAG	p.Asn232LysfsTer16	frameshift_variant	Exon 1 of 2	1	NM_005413.4	ENSP00000260653.3
ENSG00000225156	ENST00000760330.1	n.135+8424_135+8433delCCCCAGCAAG		intron_variant	Intron 1 of 1
SIX3-AS1	ENST00000760560.1	n.389-1976_389-1967delCTTGCTGGGG		intron_variant	Intron 1 of 1
SIX3-AS1	ENST00000760561.1	n.365+1578_365+1587delCTTGCTGGGG		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Holoprosencephaly 2 Pathogenic:1

Aug 29, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397515502; hg19: chr2-45169938;