rs55682875
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS1
The NM_024915.4(GRHL2):c.804C>T(p.Thr268=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000838 in 1,614,170 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00085 ( 0 hom. )
Consequence
GRHL2
NM_024915.4 synonymous
NM_024915.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.22
Genes affected
GRHL2 (HGNC:2799): (grainyhead like transcription factor 2) The protein encoded by this gene is a transcription factor that can act as a homodimer or as a heterodimer with either GRHL1 or GRHL3. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal dominant type 28 (DFNA28).[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
Variant 8-101573737-C-T is Benign according to our data. Variant chr8-101573737-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227417.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr8-101573737-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.22 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000749 (114/152298) while in subpopulation NFE AF= 0.00101 (69/68026). AF 95% confidence interval is 0.000821. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRHL2 | NM_024915.4 | c.804C>T | p.Thr268= | synonymous_variant | 6/16 | ENST00000646743.1 | |
GRHL2 | NM_001330593.2 | c.756C>T | p.Thr252= | synonymous_variant | 6/16 | ||
GRHL2 | XM_011517306.4 | c.756C>T | p.Thr252= | synonymous_variant | 6/16 | ||
GRHL2 | XM_011517307.4 | c.804C>T | p.Thr268= | synonymous_variant | 6/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRHL2 | ENST00000646743.1 | c.804C>T | p.Thr268= | synonymous_variant | 6/16 | NM_024915.4 | P1 | ||
GRHL2 | ENST00000395927.1 | c.756C>T | p.Thr252= | synonymous_variant | 6/16 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000749 AC: 114AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000740 AC: 186AN: 251478Hom.: 0 AF XY: 0.000625 AC XY: 85AN XY: 135918
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GnomAD4 exome AF: 0.000848 AC: 1239AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.000791 AC XY: 575AN XY: 727240
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GnomAD4 genome AF: 0.000749 AC: 114AN: 152298Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48AN XY: 74472
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | GRHL2: BP4, BP7 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 27, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 28, 2016 | Thr268Thr in Exon 06 of GRHL2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 58/66678 European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs55682875). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at