8-101543246-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024915.4(GRHL2):c.26A>G(p.Lys9Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,613,508 control chromosomes in the GnomAD database, including 688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 61 hom., cov: 32)

Exomes 𝑓: 0.026 ( 627 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.43

Publications

17 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):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss 28
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
posterior polymorphous corneal dystrophy
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004516661).

BP6

Variant 8-101543246-A-G is Benign according to our data. Variant chr8-101543246-A-G is described in ClinVar as Benign. ClinVar VariationId is 46218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024915.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRHL2	NM_024915.4	MANE Select	c.26A>G	p.Lys9Arg	missense	Exon 2 of 16	NP_079191.2	Q6ISB3-1
GRHL2	NM_001440447.1		c.26A>G	p.Lys9Arg	missense	Exon 2 of 16	NP_001427376.1
GRHL2	NM_001330593.2		c.-23A>G		5_prime_UTR	Exon 2 of 16	NP_001317522.1	Q6ISB3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRHL2	ENST00000646743.1	MANE Select	c.26A>G	p.Lys9Arg	missense	Exon 2 of 16	ENSP00000495564.1	Q6ISB3-1
GRHL2	ENST00000472106.2	TSL:1	n.354A>G		non_coding_transcript_exon	Exon 2 of 2
GRHL2	ENST00000907653.1		c.26A>G	p.Lys9Arg	missense	Exon 2 of 14	ENSP00000577712.1

Frequencies

GnomAD3 genomes

AF:

0.0208

AC:

3168

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.0630

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.0258

AC:

6473

AN:

251334

AF XY:

0.0258

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.0669

Gnomad FIN exome

AF:

0.0419

Gnomad NFE exome

AF:

0.0256

Gnomad OTH exome

AF:

0.0233

GnomAD4 exome

AF:

0.0263

AC:

38380

AN:

1461220

Hom.:

627

Cov.:

AF XY:

0.0261

AC XY:

18999

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.00326

AC:

109

AN:

33470

American (AMR)

AF:

0.0127

AC:

568

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

432

AN:

26128

East Asian (EAS)

AF:

0.0572

AC:

2272

AN:

39696

South Asian (SAS)

AF:

0.0206

AC:

1777

AN:

86246

European-Finnish (FIN)

AF:

0.0414

AC:

2209

AN:

53418

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0266

AC:

29577

AN:

1111402

Other (OTH)

AF:

0.0234

AC:

1412

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1832

3664

5496

7328

9160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1134

2268

3402

4536

5670

<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:

0.0208

AC:

3170

AN:

152288

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1577

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00455

AC:

189

AN:

41564

American (AMR)

AF:

0.0145

AC:

222

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3468

East Asian (EAS)

AF:

0.0631

AC:

327

AN:

5182

South Asian (SAS)

AF:

0.0180

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0433

AC:

459

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0259

AC:

1764

AN:

68020

Other (OTH)

AF:

0.0189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

157

314

471

628

785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0246

Hom.:

187

Bravo

AF:

0.0184

TwinsUK

AF:

0.0270

AC:

100

ALSPAC

AF:

0.0234

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0269

AC:

231

ExAC

AF:

0.0251

AC:

3048

Asia WGS

AF:

0.0300

AC:

103

AN:

3478

EpiCase

AF:

0.0218

EpiControl

AF:

0.0218

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

7.4

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

REVEL

Benign

0.14

Sift

Benign

0.49

Sift4G

Benign

0.27

Polyphen

0.85

Vest4

0.12

MPC

0.96

ClinPred

0.023

GERP RS

6.0

Varity_R

0.13

gMVP

0.50

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over