rs766515922

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_024915.4(GRHL2):c.685C>T(p.Arg229Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.09

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 28
Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AD Classification: STRONG Submitted by: ClinGen
posterior polymorphous corneal dystrophy
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital fibrosis of extraocular muscles
Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp

GRHL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GRHL2	NM_024915.4 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 5 of 16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2 link	c.637C>T	p.Arg213Trp	missense_variant	Exon 5 of 16		NP_001317522.1
GRHL2	NM_001440448.1 link	c.637C>T	p.Arg213Trp	missense_variant	Exon 5 of 16		NP_001427377.1
GRHL2	NM_001440447.1 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 5 of 16		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 5 of 16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1 link	c.637C>T	p.Arg213Trp	missense_variant	Exon 5 of 16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251366

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461484

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727054

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111712

Other (OTH)

AF:

0.00

AC:

AN:

60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000263657), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg229Trp variant in GRHL2 has not been previously reported in individuals with hearing loss, but has been identified in 1/16506 South Asian chromosomes a nd 1/11564 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs766515922). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. Computational prediction tools and conservation analysis do not prov ide strong support for or against an impact to the protein. In summary, the clin ical significance of the p.Arg229Trp variant is uncertain. -

not provided

Uncertain:1

Feb 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs766515922, 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: 504944). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 229 of the GRHL2 protein (p.Arg229Trp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

T;T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.53

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;.

PhyloP100

5.1

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.8

D;.;D

REVEL

Benign

0.28

Sift

Uncertain

0.021

D;.;D

Sift4G

Benign

0.16

T;.;T

Polyphen

0.21

B;B;.

Vest4

0.72

MutPred

0.63

Loss of disorder (P = 0.0347);Loss of disorder (P = 0.0347);.;

MVP

0.35

MPC

1.1

ClinPred

0.99

GERP RS

5.3

Varity_R

0.23

gMVP

0.56

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over