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GeneBe

rs398122997

chr8-101644221-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_024915.4(GRHL2):c.1609dup(p.Arg537ProfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

GRHL2
NM_024915.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.89
Variant links:
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 Pathogenic. Variant got 11 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 8-101644221-G-GC is Pathogenic according to our data. Variant chr8-101644221-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 2195.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRHL2NM_024915.4 linkuse as main transcriptc.1609dup p.Arg537ProfsTer11 frameshift_variant 13/16 ENST00000646743.1
GRHL2NM_001330593.2 linkuse as main transcriptc.1561dup p.Arg521ProfsTer11 frameshift_variant 13/16
GRHL2XM_011517306.4 linkuse as main transcriptc.1561dup p.Arg521ProfsTer11 frameshift_variant 13/16
GRHL2XM_011517307.4 linkuse as main transcriptc.1609dup p.Arg537ProfsTer11 frameshift_variant 13/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRHL2ENST00000646743.1 linkuse as main transcriptc.1609dup p.Arg537ProfsTer11 frameshift_variant 13/16 NM_024915.4 P1Q6ISB3-1
GRHL2ENST00000395927.1 linkuse as main transcriptc.1561dup p.Arg521ProfsTer11 frameshift_variant 13/162 Q6ISB3-2
GRHL2ENST00000474338.1 linkuse as main transcriptn.251dup non_coding_transcript_exon_variant 2/43
GRHL2ENST00000517674.5 linkuse as main transcriptn.264dup non_coding_transcript_exon_variant 3/45

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 28 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2002- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs398122997; hg19: chr8-102656449; API