rs10093032

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.1764-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,471,252 control chromosomes in the GnomAD database, including 102,143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11132 hom., cov: 31)

Exomes 𝑓: 0.37 ( 91011 hom. )

Consequence

GRHL2
NM_024915.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -3.67

Publications

9 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
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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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

new If you want to explore the variant's impact on the transcript NM_024915.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 8-101666570-C-T is Benign according to our data. Variant chr8-101666570-C-T is described in ClinVar as Benign. ClinVar VariationId is 261793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.521 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	Effect	Exon Rank	Protein	UniProt
GRHL2	NM_024915.4	MANE Select	c.1764-19C>T	intron	N/A	NP_079191.2	Q6ISB3-1
GRHL2	NM_001330593.2		c.1716-19C>T	intron	N/A	NP_001317522.1	Q6ISB3-2
GRHL2	NM_001440448.1		c.1716-19C>T	intron	N/A	NP_001427377.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GRHL2	ENST00000646743.1	MANE Select	c.1764-19C>T	intron	N/A	ENSP00000495564.1	Q6ISB3-1
GRHL2	ENST00000395927.1	TSL:2	c.1716-19C>T	intron	N/A	ENSP00000379260.1	Q6ISB3-2
GRHL2	ENST00000907653.1		c.1551-19C>T	intron	N/A	ENSP00000577712.1

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57324

AN:

151710

Hom.:

11114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.234

Gnomad AMR

AF:

0.415

Gnomad ASJ

AF:

0.389

Gnomad EAS

AF:

0.349

Gnomad SAS

AF:

0.541

Gnomad FIN

AF:

0.315

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.376

GnomAD2 exomes

AF:

0.390

AC:

97367

AN:

249724

AF XY:

0.392

show subpopulations

Gnomad AFR exome

AF:

0.424

Gnomad AMR exome

AF:

0.460

Gnomad ASJ exome

AF:

0.373

Gnomad EAS exome

AF:

0.348

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.345

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.366

AC:

482787

AN:

1319424

Hom.:

91011

Cov.:

AF XY:

0.370

AC XY:

245865

AN XY:

664060

show subpopulations

African (AFR)

AF:

0.431

AC:

13175

AN:

30580

American (AMR)

AF:

0.457

AC:

20287

AN:

44422

Ashkenazi Jewish (ASJ)

AF:

0.369

AC:

9333

AN:

25292

East Asian (EAS)

AF:

0.357

AC:

13929

AN:

38972

South Asian (SAS)

AF:

0.534

AC:

44545

AN:

83386

European-Finnish (FIN)

AF:

0.322

AC:

17160

AN:

53336

Middle Eastern (MID)

AF:

0.391

AC:

2165

AN:

5532

European-Non Finnish (NFE)

AF:

0.348

AC:

341361

AN:

982168

Other (OTH)

AF:

0.374

AC:

20832

AN:

55736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

16490

32980

49469

65959

82449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10630

21260

31890

42520

53150

<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:

0.378

AC:

57386

AN:

151828

Hom.:

11132

Cov.:

AF XY:

0.380

AC XY:

28215

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.424

AC:

17516

AN:

41354

American (AMR)

AF:

0.415

AC:

6335

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

1350

AN:

3466

East Asian (EAS)

AF:

0.348

AC:

1795

AN:

5154

South Asian (SAS)

AF:

0.539

AC:

2584

AN:

4796

European-Finnish (FIN)

AF:

0.315

AC:

3318

AN:

10546

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.344

AC:

23374

AN:

67924

Other (OTH)

AF:

0.377

AC:

795

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1787

3574

5360

7147

8934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.375

Hom.:

6256

Bravo

AF:

0.382

Asia WGS

AF:

0.514

AC:

1790

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Autosomal dominant nonsyndromic hearing loss 28 (1)

Corneal dystrophy, posterior polymorphous, 4 (1)

Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.18

(source)

DANN

Benign

0.55

PhyloP100

-3.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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