rs34213258

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024915.4(GRHL2):c.1572A>G(p.Pro524Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 1,614,074 control chromosomes in the GnomAD database, including 352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 171 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 181 hom. )

Consequence

GRHL2
NM_024915.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.382

Publications

7 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 8-101644185-A-G is Benign according to our data. Variant chr8-101644185-A-G is described in ClinVar as Benign. ClinVar VariationId is 178610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.382 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4 link	c.1572A>G	p.Pro524Pro	synonymous_variant	Exon 13 of 16	ENST00000646743.1	NP_079191.2	Q6ISB3-1
GRHL2	NM_001330593.2 link	c.1524A>G	p.Pro508Pro	synonymous_variant	Exon 13 of 16		NP_001317522.1	Q6ISB3-2B4DL28
GRHL2	NM_001440448.1 link	c.1524A>G	p.Pro508Pro	synonymous_variant	Exon 13 of 16		NP_001427377.1
GRHL2	NM_001440447.1 link	c.1572A>G	p.Pro524Pro	synonymous_variant	Exon 13 of 16		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GRHL2	ENST00000646743.1 link	c.1572A>G	p.Pro524Pro	synonymous_variant	Exon 13 of 16		NM_024915.4	ENSP00000495564.1	Q6ISB3-1
GRHL2	ENST00000395927.1 link	c.1524A>G	p.Pro508Pro	synonymous_variant	Exon 13 of 16	2		ENSP00000379260.1	Q6ISB3-2
GRHL2	ENST00000474338.1 link	n.214A>G		non_coding_transcript_exon_variant	Exon 2 of 4	3
GRHL2	ENST00000517674.5 link	n.227A>G		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0277

AC:

4223

AN:

152194

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0827

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.0588

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00263

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00294

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0127

AC:

3185

AN:

251318

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.0817

Gnomad AMR exome

AF:

0.00703

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.0598

Gnomad FIN exome

AF:

0.00291

Gnomad NFE exome

AF:

0.00276

Gnomad OTH exome

AF:

0.00783

GnomAD4 exome

AF:

0.00626

AC:

9152

AN:

1461762

Hom.:

181

Cov.:

AF XY:

0.00590

AC XY:

4289

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0841

AC:

2813

AN:

33466

American (AMR)

AF:

0.00751

AC:

336

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

26134

East Asian (EAS)

AF:

0.0509

AC:

2019

AN:

39674

South Asian (SAS)

AF:

0.00235

AC:

203

AN:

86248

European-Finnish (FIN)

AF:

0.00294

AC:

157

AN:

53412

Middle Eastern (MID)

AF:

0.00867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00257

AC:

2853

AN:

1111954

Other (OTH)

AF:

0.0112

AC:

677

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

485

970

1454

1939

2424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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

AF:

0.0279

AC:

4244

AN:

152312

Hom.:

171

Cov.:

AF XY:

0.0272

AC XY:

2023

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0830

AC:

3450

AN:

41552

American (AMR)

AF:

0.0135

AC:

206

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.0589

AC:

305

AN:

5178

South Asian (SAS)

AF:

0.00269

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00263

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00293

AC:

199

AN:

68034

Other (OTH)

AF:

0.0166

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

198

397

595

794

992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0146

Hom.:

Bravo

AF:

0.0321

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00207

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 08, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro524Pro in Exon 13 of GRHL2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 7.8% (292/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs34213258). -

not provided

Benign:3

Nov 09, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.3

(source)

DANN

Benign

0.76

PhyloP100

-0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over