rs200592171

Positions:

chr8-101649491-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024915.4(GRHL2):c.1690A>T(p.Met564Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000154 in 1,613,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.68

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:

GRHL2 (HGNC:):

GRHL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12266758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4 linkuse as main transcript	c.1690A>T	p.Met564Leu	missense_variant	14/16	ENST00000646743.1	NP_079191.2	Q6ISB3-1
GRHL2	NM_001330593.2 linkuse as main transcript	c.1642A>T	p.Met548Leu	missense_variant	14/16		NP_001317522.1	Q6ISB3-2B4DL28
GRHL2	XM_011517306.4 linkuse as main transcript	c.1642A>T	p.Met548Leu	missense_variant	14/16		XP_011515608.1	Q6ISB3-2
GRHL2	XM_011517307.4 linkuse as main transcript	c.1690A>T	p.Met564Leu	missense_variant	14/16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GRHL2	ENST00000646743.1 linkuse as main transcript	c.1690A>T	p.Met564Leu	missense_variant	14/16		NM_024915.4	ENSP00000495564.1	Q6ISB3-1
GRHL2	ENST00000395927.1 linkuse as main transcript	c.1642A>T	p.Met548Leu	missense_variant	14/16	2		ENSP00000379260.1	Q6ISB3-2
GRHL2	ENST00000474338.1 linkuse as main transcript	n.332A>T		non_coding_transcript_exon_variant	3/4	3
GRHL2	ENST00000517674.5 linkuse as main transcript	n.267+5266A>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000956

AC:

AN:

251112

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000158

AC:

231

AN:

1460806

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000200

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000118

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000156

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2013

Variant classified as Uncertain Significance - Favor Benign. The Met564Leu varia nt in GRHL2 has not been reported in individuals with hearing loss, but it has b een identified in 0.03% (3/8600) of European American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs200592171). Although this variant has been seen in the general popul ation, its frequency is not high enough to rule out a pathogenic role. Computati onal analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyP hen2, and SIFT) suggest that the Meth564Leu variant may not impact the protein, though these computational programs are not predictive enough to rule out pathog enicity. In summary, the clinical significance of this variant cannot be determi ned; however based upon its presence in the population and the computational pre dictions, we lean towards a more likely benign role. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GRHL2 protein function. ClinVar contains an entry for this variant (Variation ID: 163650). This variant has not been reported in the literature in individuals affected with GRHL2-related conditions. This variant is present in population databases (rs200592171, gnomAD 0.02%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 564 of the GRHL2 protein (p.Met564Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.079

T;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

.;D;D

M_CAP

Benign

0.0039

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.91

L;L;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.3

N;.;N

REVEL

Benign

0.22

Sift

Benign

0.62

T;.;T

Sift4G

Benign

0.94

T;.;T

Polyphen

0.0

B;B;.

Vest4

0.65

MutPred

0.62

Loss of catalytic residue at V560 (P = 0.0515);Loss of catalytic residue at V560 (P = 0.0515);.;

MVP

0.50

MPC

0.33

ClinPred

0.068

GERP RS

4.9

Varity_R

0.20

gMVP

0.61

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