chr8-101619683-G-A

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.1243G>A(p.Val415Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,612,456 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V415V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0073 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 269 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 10.0

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005496323).

BP6

Variant 8-101619683-G-A is Benign according to our data. Variant chr8-101619683-G-A is described in ClinVar as [Benign]. Clinvar id is 46215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4 link	c.1243G>A	p.Val415Ile	missense_variant	Exon 9 of 16	ENST00000646743.1	NP_079191.2	Q6ISB3-1
GRHL2	NM_001330593.2 link	c.1195G>A	p.Val399Ile	missense_variant	Exon 9 of 16		NP_001317522.1	Q6ISB3-2B4DL28
GRHL2	NM_001440448.1 link	c.1195G>A	p.Val399Ile	missense_variant	Exon 9 of 16		NP_001427377.1
GRHL2	NM_001440447.1 link	c.1243G>A	p.Val415Ile	missense_variant	Exon 9 of 16		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1 link	c.1243G>A	p.Val415Ile	missense_variant	Exon 9 of 16		NM_024915.4	ENSP00000495564.1		Q6ISB3-1
GRHL2	ENST00000395927.1 link	c.1195G>A	p.Val399Ile	missense_variant	Exon 9 of 16	2		ENSP00000379260.1		Q6ISB3-2

Frequencies

GnomAD3 genomes

AF:

0.00728

AC:

1108

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.0936

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0281

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.0135

AC:

3399

AN:

250920

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.00666

Gnomad EAS exome

AF:

0.100

Gnomad FIN exome

AF:

0.0293

Gnomad NFE exome

AF:

0.00199

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00526

AC:

7678

AN:

1460240

Hom.:

269

Cov.:

AF XY:

0.00514

AC XY:

3732

AN XY:

726606

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33442

American (AMR)

AF:

0.0139

AC:

621

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

173

AN:

26112

East Asian (EAS)

AF:

0.0972

AC:

3848

AN:

39598

South Asian (SAS)

AF:

0.00239

AC:

206

AN:

86222

European-Finnish (FIN)

AF:

0.0301

AC:

1606

AN:

53344

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000684

AC:

760

AN:

1110720

Other (OTH)

AF:

0.00736

AC:

444

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

343

686

1029

1372

1715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00725

AC:

1104

AN:

152216

Hom.:

Cov.:

AF XY:

0.00897

AC XY:

668

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41558

American (AMR)

AF:

0.00864

AC:

132

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.0934

AC:

484

AN:

5180

South Asian (SAS)

AF:

0.00539

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0281

AC:

297

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

67994

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

142

189

236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00442

Hom.:

Bravo

AF:

0.00663

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0129

AC:

1564

Asia WGS

AF:

0.0320

AC:

113

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 09, 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. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val415Ile in Exon 09 of GRHL2: This variant is not expected to have clinical sig nificance because it has been identified in 14.7% (25/170) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs3 779617). -

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

.;T;T

MetaRNN

Benign

0.0055

T;T;T

MetaSVM

Benign

-1.3

MutationAssessor

Uncertain

2.5

M;M;.

PhyloP100

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.53

N;.;N

REVEL

Uncertain

0.29

Sift

Benign

0.41

T;.;T

Sift4G

Benign

0.40

T;.;T

Polyphen

0.88

P;P;.

Vest4

0.39

MPC

1.0

ClinPred

0.060

GERP RS

5.8

Varity_R

0.34

gMVP

0.18

Mutation Taster

=84/16

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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chr8-101619683-G-A

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