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

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

5
5
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.84
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.41768682).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRHL2NM_024915.4 linkc.641G>A p.Ser214Asn missense_variant Exon 4 of 16 ENST00000646743.1 NP_079191.2 Q6ISB3-1
GRHL2NM_001330593.2 linkc.593G>A p.Ser198Asn missense_variant Exon 4 of 16 NP_001317522.1 Q6ISB3-2B4DL28
GRHL2XM_011517306.4 linkc.593G>A p.Ser198Asn missense_variant Exon 4 of 16 XP_011515608.1 Q6ISB3-2
GRHL2XM_011517307.4 linkc.641G>A p.Ser214Asn missense_variant Exon 4 of 16 XP_011515609.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GRHL2ENST00000646743.1 linkc.641G>A p.Ser214Asn missense_variant Exon 4 of 16 NM_024915.4 ENSP00000495564.1 Q6ISB3-1
GRHL2ENST00000395927.1 linkc.593G>A p.Ser198Asn missense_variant Exon 4 of 16 2 ENSP00000379260.1 Q6ISB3-2

Frequencies

GnomAD3 genomes
AF:
0.0000985
AC:
15
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000678
AC:
17
AN:
250670
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135658
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000925
Gnomad NFE exome
AF:
0.000133
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000835
AC:
122
AN:
1461830
Hom.:
0
Cov.:
33
AF XY:
0.0000880
AC XY:
64
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000103
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.0000680
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 19, 2024This 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 28, 2024In 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 -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 11, 2018The 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
Uncertain significance, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinAug 05, 2022ACMG classification criteria: BP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.39
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
.;D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.42
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Pathogenic
3.1
M;M;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.8
N;.;N
REVEL
Benign
0.22
Sift
Uncertain
0.0010
D;.;D
Sift4G
Uncertain
0.0080
D;.;D
Polyphen
1.0
D;D;.
Vest4
0.57
MVP
0.38
MPC
1.1
ClinPred
0.76
D
GERP RS
5.3
Varity_R
0.51
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs199931364; hg19: chr8-102571003; API