rs142411476

Positions:

• chr8-101558682-G-A

Variant summary

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

The NM_024915.4(GRHL2):​c.548G>A​(p.Arg183Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000203 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08277768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.548G>A	p.Arg183Gln	missense_variant	4/16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.500G>A	p.Arg167Gln	missense_variant	4/16		NP_001317522.1
GRHL2	XM_011517306.4	c.500G>A	p.Arg167Gln	missense_variant	4/16		XP_011515608.1
GRHL2	XM_011517307.4	c.548G>A	p.Arg183Gln	missense_variant	4/16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.548G>A	p.Arg183Gln	missense_variant	4/16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.500G>A	p.Arg167Gln	missense_variant	4/16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152146 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251330 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135824

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.000231 AC XY: 168 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000231

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152264 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 29, 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: 178378). This variant has not been reported in the literature in individuals affected with GRHL2-related conditions. This variant is present in population databases (rs142411476, gnomAD 0.04%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 183 of the GRHL2 protein (p.Arg183Gln). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with GRHL2-related disorders to our knowledge; This variant is associated with the following publications: (PMID: 36596879) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 12, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Arg183Gln var iant in GRHL2 has been identified by our laboratory in one individual with heari ng loss, but did not segregate with the disease in an affected relative (LMM unp ublished data). It has been identified in 27/66684 European chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14241 1476). Computational prediction tools and conservation analysis suggest that the p.Arg183Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical sign ificance of the p.Arg183Gln variant is uncertain, these data suggest that it is more likely to be benign. -

Autosomal dominant nonsyndromic hearing loss 28;C4014987:Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome;C4747961:Corneal dystrophy, posterior polymorphous, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.78	N;.;N
REVEL	Benign	0.12
Sift	Benign	0.30	T;.;T
Sift4G	Benign	0.63	T;.;T
Polyphen		0.90	P;P;.
Vest4		0.48
MVP		0.13
MPC		0.57
ClinPred		0.10	T
GERP RS		5.3
Varity_R		0.084
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs142411476; hg19: chr8-102570910; COSMIC: COSV52547381; COSMIC: COSV52547381;