chr2-219055221-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_002181.4(IHH):c.1222G>A(p.Gly408Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000759 in 1,581,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002181.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IHH | NM_002181.4 | c.1222G>A | p.Gly408Arg | missense_variant | 3/3 | ENST00000295731.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IHH | ENST00000295731.7 | c.1222G>A | p.Gly408Arg | missense_variant | 3/3 | 1 | NM_002181.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000117 AC: 23AN: 195964Hom.: 0 AF XY: 0.000103 AC XY: 11AN XY: 106282
GnomAD4 exome AF: 0.0000728 AC: 104AN: 1429494Hom.: 0 Cov.: 30 AF XY: 0.0000678 AC XY: 48AN XY: 708342
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152356Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 408 of the IHH protein (p.Gly408Arg). This variant is present in population databases (rs200216644, gnomAD 0.05%). This missense change has been observed in individuals with brachydactyly (PMID: 35846898; Invitae). ClinVar contains an entry for this variant (Variation ID: 898206). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Brachydactyly type A1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at