rs142411476

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024915.4(GRHL2):c.548G>A(p.Arg183Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000203 in 1,614,158 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 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.22

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]

GRHL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08277768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4 link	c.548G>A	p.Arg183Gln	missense_variant	Exon 4 of 16	ENST00000646743.1	NP_079191.2	Q6ISB3-1
GRHL2	NM_001330593.2 link	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 16		NP_001317522.1	Q6ISB3-2B4DL28
GRHL2	XM_011517306.4 link	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 16		XP_011515608.1	Q6ISB3-2
GRHL2	XM_011517307.4 link	c.548G>A	p.Arg183Gln	missense_variant	Exon 4 of 16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1 link	c.548G>A	p.Arg183Gln	missense_variant	Exon 4 of 16		NM_024915.4	ENSP00000495564.1		Q6ISB3-1
GRHL2	ENST00000395927.1 link	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 16	2		ENSP00000379260.1		Q6ISB3-2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000235

AC:

AN:

251330

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000208

AC:

304

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

168

AN XY:

727248

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:

0.000209

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000151

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000311

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000382

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

Jun 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 183 of the GRHL2 protein (p.Arg183Gln). This variant is present in population databases (rs142411476, gnomAD 0.04%). 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: 178378). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Sep 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with GRHL2-related disorders to our knowledge; This variant is associated with the following publications: (PMID: 36596879) -

not specified

Uncertain:1

Nov 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Arg183Gln var iant in GRHL2 has been identified by our laboratory in one individual with heari ng loss, but did not segregate with the disease in an affected relative (LMM unp ublished data). It has been identified in 27/66684 European chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14241 1476). Computational prediction tools and conservation analysis suggest that the p.Arg183Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical sign ificance of the p.Arg183Gln variant is uncertain, these data suggest that it is more likely to be benign. -

Autosomal dominant nonsyndromic hearing loss 28;C4014987:Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome;C4747961:Corneal dystrophy, posterior polymorphous, 4

Uncertain:1

Oct 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

T;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Benign

0.0094

MetaRNN

Benign

0.083

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.78

N;.;N

REVEL

Benign

0.12

Sift

Benign

0.30

T;.;T

Sift4G

Benign

0.63

T;.;T

Polyphen

0.90

P;P;.

Vest4

0.48

MVP

0.13

MPC

0.57

ClinPred

0.10

GERP RS

5.3

Varity_R

0.084

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over