chr8-101558775-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_024915.4(GRHL2):c.641G>A(p.Ser214Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_024915.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRHL2 | NM_024915.4 | c.641G>A | p.Ser214Asn | missense_variant | Exon 4 of 16 | ENST00000646743.1 | NP_079191.2 | |
GRHL2 | NM_001330593.2 | c.593G>A | p.Ser198Asn | missense_variant | Exon 4 of 16 | NP_001317522.1 | ||
GRHL2 | XM_011517306.4 | c.593G>A | p.Ser198Asn | missense_variant | Exon 4 of 16 | XP_011515608.1 | ||
GRHL2 | XM_011517307.4 | c.641G>A | p.Ser214Asn | missense_variant | Exon 4 of 16 | XP_011515609.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000985 AC: 15AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000678 AC: 17AN: 250670Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135658
GnomAD4 exome AF: 0.0000835 AC: 122AN: 1461830Hom.: 0 Cov.: 33 AF XY: 0.0000880 AC XY: 64AN XY: 727208
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:2
In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 214 of the GRHL2 protein (p.Ser214Asn). This variant is present in population databases (rs199931364, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GRHL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 228733). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GRHL2 protein function with a negative predictive value of 80%. 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. -
not specified Uncertain:1
The p.Ser214Asn variant in GRHL2 has been reported in 1 individual with mild sen sorineural hearing loss (LMM data). This variant has been identified in 14/12629 2 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs199931364). Computational prediction tools and cons ervation analysis suggest that the p.Ser214Asn variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, the clinical significance of the p.Ser214Asn variant is uncertain. ACMG/ AMP Criteria applied: PM2_Supporting, PP3 -
Corneal dystrophy, posterior polymorphous, 4 Uncertain:1
ACMG classification criteria: BP4 supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at