2-44942780-C-G

Variant names:

• chr2-44942780-C-G
• rs121917878
• NM_005413.4:c.676C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_005413.4(SIX3):​c.676C>G​(p.Leu226Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L226L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.77
• Publications: 6 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity SIX3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005413.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 2-44942780-C-G is Pathogenic according to our data. Variant chr2-44942780-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6093.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	NM_005413.4	MANE Select	c.676C>G	p.Leu226Val	missense	Exon 1 of 2	NP_005404.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.676C>G	p.Leu226Val	missense	Exon 1 of 2	ENSP00000260653.3
	ENSG00000225156	ENST00000760330.1		n.135+8404C>G		intron	N/A
	SIX3-AS1	ENST00000760560.1		n.389-1947G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Holoprosencephaly 2 Pathogenic:2

Dec 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Aug 29, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.028
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.69	N
PhyloP100		4.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.74
Sift	Benign	0.045	D
Sift4G	Benign	0.17	T
Polyphen		0.39	B
Vest4		0.79
MutPred		0.71		Gain of MoRF binding (P = 0.0911)
MVP		0.94
MPC		2.2
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.71
gMVP		0.84
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: -5

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

Other links and lift over

dbSNP: rs121917878; hg19: chr2-45169919;