Variant 8-101543297-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_024915.4(GRHL2):c.77G>A(p.Arg26Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.38

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GRHL2	NM_024915.4 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	2/16	ENST00000646743.1
GRHL2	NM_001330593.2 linkuse as main transcript	c.29G>A	p.Arg10Gln	missense_variant	2/16
GRHL2	XM_011517306.4 linkuse as main transcript	c.29G>A	p.Arg10Gln	missense_variant	2/16
GRHL2	XM_011517307.4 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	2/16		NM_024915.4	P1	Q6ISB3-1
GRHL2	ENST00000472106.2 linkuse as main transcript	n.405G>A		non_coding_transcript_exon_variant	2/2	1
GRHL2	ENST00000395927.1 linkuse as main transcript	c.29G>A	p.Arg10Gln	missense_variant	2/16	2			Q6ISB3-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251186

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1420619). This variant has not been reported in the literature in individuals affected with GRHL2-related conditions. This variant is present in population databases (rs750332552, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 26 of the GRHL2 protein (p.Arg26Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

0.0060

BayesDel_noAF

Uncertain

-0.050

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.34

T;T;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.6

N;.;N

REVEL

Uncertain

0.34

Sift

Benign

0.14

T;.;T

Sift4G

Benign

0.14

T;.;T

Polyphen

1.0

D;D;.

Vest4

0.72

MutPred

0.12

Gain of glycosylation at P21 (P = 0.1215);Gain of glycosylation at P21 (P = 0.1215);.;

MVP

0.38

MPC

1.2

ClinPred

0.95

GERP RS

6.0

Varity_R

0.21

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