21-36723048-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_005069.6(SIM2):āc.461A>Gā(p.Tyr154Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Consequence
NM_005069.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SIM2 | NM_005069.6 | c.461A>G | p.Tyr154Cys | missense_variant | Exon 5 of 11 | ENST00000290399.11 | NP_005060.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SIM2 | ENST00000290399.11 | c.461A>G | p.Tyr154Cys | missense_variant | Exon 5 of 11 | 1 | NM_005069.6 | ENSP00000290399.6 | ||
SIM2 | ENST00000431229.1 | c.272A>G | p.Tyr91Cys | missense_variant | Exon 4 of 10 | 1 | ENSP00000392003.1 | |||
SIM2 | ENST00000481185.1 | n.1074A>G | non_coding_transcript_exon_variant | Exon 5 of 10 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251426Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135898
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461596Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 727140
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74454
ClinVar
Submissions by phenotype
Neurodevelopmental with craniofacial anomalies disorder Pathogenic:1
The Tyr154Cys homozygous missense variant in SIM2 was found by whole genome sequencing in a boy with multiple craniofacial anomalies, global developmental delay, and intellectual impairment. The identified variant is very rare (ExAC AF 2.47E-5, gnomAD AF 9.85E-5, GME AF 5.04E-4) and segregating in the family in an autosomal recessive inheritance. Both parents and two unaffected sisters were heterozygous for the variant, while the unaffected brother was homozygous for the reference allele. Additionally, functional studies on zebrafish showed that the Tyr154Cys variant caused craniofacial abnormalities mimicking the patient's phenotype. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at