rs3735709

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 46218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-101543246-A-G is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GRHL2	NM_024915.4 linkuse as main transcript	c.26A>G	p.Lys9Arg	missense_variant	2/16	ENST00000646743.1	NP_079191.2
GRHL2	XM_011517307.4 linkuse as main transcript	c.26A>G	p.Lys9Arg	missense_variant	2/16		XP_011515609.1
GRHL2	NM_001330593.2 linkuse as main transcript	c.-23A>G		5_prime_UTR_variant	2/16		NP_001317522.1
GRHL2	XM_011517306.4 linkuse as main transcript	c.-23A>G		5_prime_UTR_variant	2/16		XP_011515608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1 linkuse as main transcript	c.26A>G	p.Lys9Arg	missense_variant	2/16		NM_024915.4	ENSP00000495564	P1	Q6ISB3-1
GRHL2	ENST00000472106.2 linkuse as main transcript	n.354A>G		non_coding_transcript_exon_variant	2/2	1
GRHL2	ENST00000395927.1 linkuse as main transcript	c.-23A>G		5_prime_UTR_variant	2/16	2		ENSP00000379260		Q6ISB3-2

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

GnomAD3 exomes

AF:

0.0258

AC:

6473

AN:

251334

Hom.:

123

AF XY:

0.0258

AC XY:

3503

AN XY:

135846

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 SAS exome

AF:

0.0213

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

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0165

Gnomad4 EAS exome

AF:

0.0572

Gnomad4 SAS exome

AF:

0.0206

Gnomad4 FIN exome

AF:

0.0414

Gnomad4 NFE exome

AF:

0.0266

Gnomad4 OTH exome

AF:

0.0234

GnomAD4 genome

AF:

0.0208

AC:

3170

AN:

152288

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1577

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00455

Gnomad4 AMR

AF:

0.0145

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.0631

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.0433

Gnomad4 NFE

AF:

0.0259

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0248

Hom.:

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Lys9Arg in Exon 02 of GRHL2: This variant is not expected to have clinical signi ficance because it has been identified in 2.8% (194/7020) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs3735709). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

.;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.14

Sift

Benign

0.49

T;.

Sift4G

Benign

0.27

T;.

Polyphen

0.85

P;P

Vest4

0.12

MPC

0.96

ClinPred

0.023

GERP RS

6.0

Varity_R

0.13

gMVP

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over