2-44944648-C-T

Position:

• chr2-44944648-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005413.4(SIX3):​c.887C>T​(p.Ser296Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000703 in 1,422,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24843165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX3	NM_005413.4	c.887C>T	p.Ser296Leu	missense_variant	2/2	ENST00000260653.5	NP_005404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX3	ENST00000260653.5	c.887C>T	p.Ser296Leu	missense_variant	2/2	1	NM_005413.4	ENSP00000260653.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422054 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 705998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000278

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000859 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.34
Sift	Benign	0.036	D
Sift4G	Uncertain	0.033	D
Polyphen		0.013	B
Vest4		0.24
MutPred		0.22		Loss of phosphorylation at S296 (P = 0.0093);
MVP		0.94
MPC		1.1
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.24
gMVP		0.65

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: rs751280287; hg19: chr2-45171787;